Indazole-based protac degraders and their anticancer activity

Abstract

Provided herein are compounds of formula (I), wherein R1, R2, R6, R7, D1, Q6, Q8, A, Y, Z, m, and z are defined herein, and pharmaceutically acceptable salts thereof: formula (I), Also provided are pharmaceutical compositions containing one or more compound described herein and methods of using the compounds.

Description

120039.000146 | TYRA.037PCT PROTAC DEGRADERS AND METHODS OF THEIR USE CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of United States Provisional Application No.63 / 636,630, filed April 19, 2024, and of United States Provisional Application No. 63 / 677,091, filed July 30, 2024, each of which is incorporated by reference herein in its entirety. TECHNICAL FIELD

[0002] The disclosure pertains to compounds, pharmaceutical compositions that include one or more such compounds, and methods of using such compounds in treating cancer. BACKGROUND

[0003] Kinase inhibitors have been used to block the activity of kinases and thereby treat cancer (e.g., by inhibiting mitotic processes). These kinase inhibitors are often small molecules that target kinases to block the development, growth or spread of cancer. However, although various inhibitors of kinases are known, there remains a need for new compounds to be used for the treatment of diseases such as hyper-proliferative diseases. SUMMARY

[0004] In some embodiments, the disclosure provides compounds of formula (I), wherein R1, R2, R6, R7, D1, Q6, Q8, A, Y, Z, m, and z are defined herein, and pharmaceutically acceptable salts thereof:- 1 -120039.000146 | TYRA.037PCT

[0005] In other embodiments, the disclosure provides pharmaceutical compositions containing one or more compound described herein.

[0006] In further embodiments, methods of using the compounds are described. DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0007] The disclosure may be more fully appreciated by reference to the following description, including the following definitions and examples. Certain features of the disclosed compositions and methods which are described herein in the context of separate aspects, may also be provided in combination in a single aspect. Alternatively, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single aspect, may also be provided separately or in any subcombination.

[0008] The term “optionally substituted,” or “substituted” as used herein to describe a substituent defined herein, means that the substituent may, but is not required to be, substituted with one or more of: halo (i.e., F, Cl, Br, I), cyano (CN), OH, C1-6alkyl, C3-6cycloalkyl, 3-7 membered heterocycloalkyl, C3-6spirocycloalkyl, 3-7 membered spiroheterocycloalkyl, bridged cycloalkyl, bridged heterocycloalkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl (e.g., CF3, CHF2, CH2CF3, and the like), C1-6alkoxy, C1-6haloalkoxy (e.g., OCF3, OCHF2, OCH2CF3, and the like), C1-6alkylthio (e.g., SCH3, SCH2CH3, and the like), C1-6alkylamino (e.g., CH2NH2, CH2CH2NH2, and the like), NH2, -NH(C1-6alkyl), -N(C1- 6alkyl)2, -NH(C1-6 alkoxy), -C(O)NHC1-6alkyl, -C(O)N(C1-6 alkyl)2, -COOH, -C1-6alkylCOOH, -C3-6cycloalkylCOOH, -C(O)NH2, -C1-6alkylCONH2,-C3-6cycloalkylCONH2, - C1-6alkylCONHC1-6alkyl, -C1-6alkylCON(C1-6alkyl)2,-C(O)C1-6alkyl, -C(O)OC1-6alkyl, - NHCO(C1-6alkyl), -N(C1-6alkyl)C(O)(C1-6alkyl), -S(O)C1-6alkyl, -S(O)2C1-6 alkyl, oxo (i.e., =O), 6-12 membered aryl, or 5 to 12 membered heteroaryl groups. In other embodiments, “optionally substituted,” or “substituted” means that the substituent may, but is not required to be, substituted with one or more of -C(O)(C1-6haloalkyl), -NHSO2(C1-6alkyl), -N(C1- 6alkyl)SO2(C1-6alkyl), or -P(O)(C1-6alkyl)2 (e.g., -P(O)(CH3)2). In some embodiments, each of the above optional substituents are themselves optionally substituted by one or two of these groups.

[0009] When a range of carbon atoms is used herein, for example, C1-6, all ranges, as well as individual numbers of carbon atoms are encompassed. For example, “C1-3” includes C1-3, C1-2, C2-3, C1, C2, and C3. Thus, for example, a “C1-4alkyl” refers to all alkyl groups having from 1 to 4 carbons (e.g., 1, 2, 3, or 4), that is, CH3, CH3CH2, CH3CH2CH2, - 2 -4896-4398-0599.1120039.000146 | TYRA.037PCT (CH3)2CH, CH3CH2CH2CH2, CH3CH2CH(CH3) and (CH3)3C. A “C1-6alkyl” refers to all alkyl groups having from 1 to 6 carbons (e.g., 1, 2, 3, 4, 5, or 6).

[0010] As used herein, the term “alkyl” refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety may be branched or straight chain. Examples of branched alkyl groups include, but are not limited to, iso-propyl, sec-butyl, t-butyl and the like. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n- propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and the like. The alkyl group may have 1 to 30 carbon atoms (whenever it appears herein, a numerical range such as “1 to 30” refers to each integer in the given range; e.g., “1 to 30 carbon atoms” means that the alkyl group may consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The “alkyl” group may also be a medium size alkyl having 1 to 12 carbon atoms. The “alkyl” group could also be a lower alkyl having 1 to 6 carbon atoms. By way of example only, “C1-5alkyl” indicates that there are one to five carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight- chained), etc. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl. In several embodiments, “Me” is methyl (e.g., CH3). An alkyl group may be substituted or unsubstituted as described herein.

[0011] As used herein, “alkenyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. Alkenyl groups may contain 2 to 12 carbon atoms. For example, a C2-6alkenyl group indicates that there two to six carbon atoms, that is, a propenyl, butenyl, pentenyl, or hexenyl group. An alkenyl group may be unsubstituted or substituted as described herein.

[0012] As used herein, “alkynyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. Alkynyl groups may contain 2 to 12 carbon atoms. For example, a C2-6alkynyl group indicates that there two to six carbon atoms, that is, a propynyl, butynyl, pentynyl, or hexynyl group. An alkynyl group may be unsubstituted or substituted.

[0013] As used herein, the term “alkoxy” refers to a O-alkyl, wherein alkyl is defined herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, - 3 -4896-4398-0599.1120039.000146 | TYRA.037PCT n-propoxy, n-butoxy, n-pentoxy, n-hexoxy, n-heptoxy and the like. In several embodiments, “OMe” is methoxy (e.g., OCH3). An alkoxy group may be substituted or unsubstituted as described herein.

[0014] As used herein, the term “heteroalkyl” refers to a fully saturated aliphatic hydrocarbon group containing one or more heteroatom. The heteroatom may be oxygen, nitrogen, or sulfur. The heteroalkyl moiety may be branched or straight chain. The heteroalkyl group may have 1 to 30 atoms (whenever it appears herein, a numerical range such as “1 to 30” refers to each integer in the given range; e.g., “1 to 30 atoms” means that the heteroalkyl group may consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 atoms, although the present definition also covers the occurrence of the term “heteroalkyl” where no numerical range is designated). The “heteroalkyl” group may also be a medium size alkyl having 1 to 12 atoms. The “heteroalkyl” group could also be a lower alkyl having 1 to 6 atoms. A heteroalkyl may be substituted or unsubstituted as described herein.

[0015] As used herein, “cycloalkyl” refers to a completely saturated (no double or triple bonds) mono- or multi-cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused fashion. Cycloalkyl groups may contain 3 to 12 carbon atoms. For example, a C3-6cycloalkyl group indicates that there three to six carbon atoms in the ring, that is, the ring is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group. A cycloalkyl group may be substituted as defined herein. A cycloalkyl may be unsubstituted or substituted as described herein.

[0016] As used herein, the term “spirocycloalkyl ring” refers to a cycloalkyl ring that shares one carbon atom with another cyclic ring. For example, a 3-7 membered spirocycloalkyl ring indicates that there are 3, 4, 5, 6, or 7 carbon atoms in the cycloalkyl ring that shares a single carbon atom in common with another cyclic ring. By way of example, shown below are exemplary 3-7 membered spirocycloalkyl groups attached to a piperidine ring:. A spirocycloalkyl may be unsubstituted or substituted as described herein. - 4 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0017] As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings. The number of carbon atoms in an aryl group can vary. For example, the aryl can be a C6-14 aryl, a C6-10 aryl, or a C6 aryl. Examples of aryl groups include, but are not limited to, phenyl, naphthyl and azulenyl. An aryl may be substituted or unsubstituted as described herein.

[0018] As used herein, “heteroaryl” refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur. The number of atoms in the ring(s) of a heteroaryl group can vary. For example, the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s). Furthermore, the term “heteroaryl” includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. Heteroaryl rings may also include bridge head nitrogen atoms. For example but not limited to: pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyridine, and pyrazolo[1,5-a]pyrimidine. A heteroaryl group may be substituted or unsubstituted. A heteroaryl may be unsubstituted or substituted as described herein.

[0019] As used herein, “heterocycloalkyl” refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic, and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system. A heterocycloalkyl may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings. The heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur, and nitrogen. A heterocycloalkyl may further contain one or more carbonyl or - 5 -4896-4398-0599.1120039.000146 | TYRA.037PCT thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio- systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused fashion. Additionally, any nitrogens in a heterocycloalkyl may be quaternized. Heterocycloalkyl groups may be unsubstituted or substituted. Examples of such “heterocycloalkyl” groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3- dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3- dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-Oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline, 3,4-methylenedioxyphenyl). A heterocycloalkyl may be unsubstituted or substituted as described herein.

[0020] As used herein, the term “spiroheterocycloalkyl ring” refers to a heterocycloalkyl ring that shares one carbon atom with another cyclic ring. For example, a 3- 7 membered spiroheterocycloalkyl ring indicates that there are 3, 4, 5, 6, or 7 atoms in the heterocycloalkyl ring, and only one of the carbon atoms in that heterocycloalkyl ring is also a member of another cyclic ring. By way of example, shown below are exemplary 3-7 membered spiroheterocycloalkyl groups attached to a piperidine ring:. A spiroheterocycloalkyl may be unsubstituted or substituted as described herein.

[0021] As used herein, the term “bridged bicyclic ring,” refers to a ring system comprising two joined cycloalkyl or heterocycloalkyl rings that share at least three at least three atoms For example, a 6-9 membered bridged bicyclic ring indicates that there are 6, 7, 8, or 9 atoms in the bridged bicyclic ring. By way of example, shown below are exemplary 6-9 membered bridged bicyclic rings: - 6 -4896-4398-0599.1120039.000146 | TYRA.037PCT. A bridged bicyclic ring may be unsubstituted or substituted as described herein.

[0022] As used herein, the term “amino” refers to a –NH2 group.

[0023] As used herein, the term “hydroxy” refers to a –OH group.

[0024] As used herein, the term “halogen” or “halo” refers to fluorine, chlorine, bromine or iodine.

[0025] The term “pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In several embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine. Other pharmaceutically acceptable salts include the trifluoroacetic acid salt.

[0026] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In addition, it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each - 7 -4896-4398-0599.1120039.000146 | TYRA.037PCT double bond may independently be E or Z a mixture thereof. It is understood that, in any compound described herein having one or more chiral centers, all possible diastereomers are also envisioned. It is understood that, in any compound described herein all tautomers are envisioned. It is also understood that, in any compound described herein, all isotopes of the included atoms are envisioned. For example, any instance of hydrogen, may include hydrogen-1 (protium), hydrogen-2 (deuterium), hydrogen-3 (tritium) or other isotopes; any instance of carbon may include carbon-12, carbon-13, carbon-14, or other isotopes; any instance of oxygen may include oxygen-16, oxygen-17, oxygen-18, or other isotopes; any instance of fluorine may include one or more of fluorine-18, fluorine-19, or other isotopes; any instance of sulfur may include one or more of sulfur-32, sulfur-34, sulfur-35, sulfur-36, or other isotopes.

[0027] As used herein, the term “kinase inhibitor” means any compound, molecule or composition that inhibits or reduces the activity of a kinase. The inhibition can be achieved by, for example, blocking phosphorylation of the kinase (e.g., competing with adenosine triphosphate (ATP), a phosphorylating entity), by binding to a site outside the active site, affecting its activity by a conformational change, or by depriving kinases of access to the molecular chaperoning systems on which they depend for their cellular stability, leading to their ubiquitylation and degradation.

[0028] As used herein, “subject,” “host,” “patient,” and “individual” are used interchangeably and shall be given its ordinary meaning and shall also refer to an organism that has FGFR proteins. This includes mammals, e.g., a human, a non-human primate, ungulates, canines, felines, equines, mice, rats, and the like. The term “mammal” includes both human and non-human mammals.

[0029] The term “sample” or “biological sample” shall be given its ordinary meaning and also encompasses a variety of sample types obtained from an organism and can be used in an imaging, a diagnostic, a prognostic, or a monitoring assay. The term encompasses blood and other liquid samples of biological origin, solid tissue samples, such as a biopsy specimen or tissue cultures or cells derived therefrom and the progeny thereof. The term encompasses samples that have been manipulated in any way after their procurement, such as by treatment with reagents, solubilization, or enrichment for certain components. The term encompasses a clinical sample, and also includes cells in cell culture, cell supernatants, cell lysates, serum, plasma, biological fluids, and tissue samples. - 8 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0030] The terms “treatment,” “treating,” “treat” and the like shall be given its ordinary meaning and shall also include herein to generally refer to obtaining a desired pharmacologic and / or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or may be therapeutic in terms of a partial or complete stabilization or cure for a disease and / or adverse effect attributable to the disease. “Treatment” as used herein shall be given its ordinary meaning and shall also cover any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease or symptom from occurring in a subject which may be predisposed to the disease or symptom but has not yet been diagnosed as having it; (b) inhibiting the disease symptom, e.g., arresting its development; and / or (c) relieving the disease symptom, e.g., causing regression of the disease or symptom.

[0031] The terms “cancer,” “neoplasm,” and “tumor” are used interchangeably herein, shall be given its ordinary meaning and shall also refer to cells which exhibit relatively autonomous growth, so that they exhibit an aberrant growth phenotype characterized by a significant loss of control of cell proliferation. In general, cells of interest for detection or treatment include precursors, precancerous (e.g., benign), malignant, pre- metastatic, metastatic, and non-metastatic cells. As used herein, “FGFR related cancer” denotes those cancers that involve an increased activity in a mutant FGFR kinase, for example, the continued activation of FGFR.

[0032] The term “control” refers shall be given its ordinary meaning and shall also include a sample or standard used for comparison with a sample which is being examined, processed, characterized, analyzed, etc. In several embodiments, the control is a sample obtained from a healthy patient or a non-tumor tissue sample obtained from a patient diagnosed with a tumor. In several embodiments, the control is a historical control or standard reference value or range of values. In several embodiments, the control is a comparison to a wild-type FGFR arrangement or scenario.

[0033] With respect to the use of substantially any plural and / or singular terms herein, those having skill in the art can translate from the plural to the singular and / or from the singular to the plural as is appropriate to the context and / or application. The various singular / plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of - 9 -4896-4398-0599.1120039.000146 | TYRA.037PCT these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope. Compounds

[0034] In some aspects, the disclosure is directed to compounds of formula (I), or a pharmaceutically acceptable salt thereof:

[0035] According to the disclosure, n is 1, 2, or 3. In some embodiments, n is 1. In other embodiments, n is 2. In further embodiments, n is 3.

[0036] According to the disclosure, m is 0, 1, 2, or 3. In some embodiments, m is 0. In other embodiments, m is 1. In further embodiments, m is 2. In still other embodiments, m is 3.

[0037] According to the disclosure, each R1is, independently, H, CN, or optionally substituted C1-6alkyl. In some embodiments, R1is H. In other embodiments, R1is CN. In further embodiments, R1is optionally substituted C1-6alkyl, such as methyl, or ethyl, or propyl, or butyl, or pentyl, or hexyl. In other embodiments, two R1groups attached to the same carbon atom, together with the carbon atom to which they are both attached form an optionally substituted 3-7 membered spirocycloalkyl or an optionally substituted 3-7 membered spiroheterocycloalkyl. In further embodiments, two R1groups attached to the same carbon atom, together with that carbon atom, form a carbonyl group (C=O). In yet other embodiments, or two R1groups attached to different carbon atoms, together with the carbon atoms to which they are attached, form a 3-7 membered cycloalkyl.

[0038] According to the disclosure, each R2is, independently, H, CN, or optionally substituted C1-6alkyl. In some embodiments, R2is H. In other embodiments, R2is CN. In - 10 -4896-4398-0599.1120039.000146 | TYRA.037PCT further embodiments, R2is optionally substituted C1-6alkyl, such as methyl, or ethyl, or propyl, or butyl, or pentyl, or hexyl. In other embodiments, two R2groups attached to the same carbon atom, together with the carbon atom to which they are both attached form an optionally substituted 3-7 membered spirocycloalkyl or an optionally substituted 3-7 membered spiroheterocycloalkyl. In further embodiments, two R2groups attached to the same carbon atom, together with that carbon atom, form a carbonyl group (C=O). In yet other embodiments, or two R2groups attached to different carbon atoms, together with the carbon atoms to which they are attached, form a 3-7 membered cycloalkyl.

[0039] In some embodiments, an R1group and an R2group are attached to form a 6- 9 membered bridged bicyclic ring.

[0040] According to the disclosure, A is N or CH. In some embodiments, A is N. In other embodiments, A is CH.

[0041] According to the disclosure, Y is a 5-membered heteroaryl, 6-membered heteroaryl, or a 6-membered aryl. In some embodiments, Y is a 5-membered heteroaryl. In other embodiments, Y is 6-membered heteroaryl, such as pyridyl. In further embodiments, Y is 6-membered aryl.

[0042] According to the disclosure, Q6and Q8are each, independently, N or CR5. In some embodiments, Q6is N. In other embodiments, Q8is N. In further embodiments, Q8is CR5. In yet other embodiments, Q6is CR5.

[0043] According to the disclosure, R5is H, halo, C1-3alkyl, C1-3alkoxy, or cycloalkyl. In some embodiments, R5is H. In other embodiments, R5is halo, such as Cl, or such as F, or such as Br. In further embodiments, R5is C1-3alkyl, such as methyl, or ethyl, or propyl. In still further embodiments, R5is C1-3alkoxy, such as methoxy, or ethoxy, or propoxy. In yet other embodiments, R5is cycloalkyl, such as cyclopropyl, or cyclobutyl, or cyclopentyl, or cyclohexyl.

[0044] According to the disclosure, D1is O or NRB, wherein RBis H or C1-3alkyl. In some embodiments, D1is O. In other embodiments, D is NRB. In further embodiments, RBis H. In yet other embodiments, RBis C1-3alkyl, such as methyl, or such as ethyl, or such as propyl.

[0045] According to the disclosure, Z is NR3or CR4R4’. In some embodiments, Z is NR3. In other embodiments, Z is CR4R4’.

[0046] According to the disclosure, R3is a bond to L. - 11 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0047] According to the disclosure, R4is H, F, CN, or optionally substituted C1- 6alkyl. In some embodiments, R4is H. In other embodiments, R4is F. In further embodiments, R4is CN. In yet other embodiments, R4is optionally substituted C1-6alkyl, such as methyl, or ethyl, or propyl, or butyl, or pentyl, or hexyl.

[0048] According to the disclosure, R4’is R3, OR3, NHR3, or -NR3(C1-3alkyl). In some embodiments, R4’is R3. In other embodiments, R4’is OR3. In further embodiments, R4’is NHR3. In yet other embodiments, R4’is -NR3(C1-3alkyl), such as -NR3(CH3), or such as -NR3(CH2CH3), or such as -NR3(propyl)

[0049] In certain embodiments, R4and R4’, together with the C atom to which they are both attached, form a substituted 3- to 7-membered heterocycloalkyl or a substituted 3- to 7-membered cycloalkyl. The substituted 3- to 7-membered heterocycloalkyl or the substituted 3- to 7-membered cycloalkyl is substituted with one R3. In addition to R3, the 3- to 7-membered heterocycloalkyl or cycloalkyl may be substituted with other groups as described above. In some embodiments, R4and R4’together form an substituted 3- to 7- membered heterocycloalkyl, e.g., azetidinyl, piperazinyl, or piperidinyl, that is substituted with one R3. In other embodiments, R4and R4’together form an substituted 3- to 7- membered cycloalkyl, e.g., cyclopropyl, cyclobutyl, or cyclopentyl, that is substituted with one R3.

[0050] According to the disclosure, R6is C1-6alkyl. In some embodiments, R6is methyl. In other embodiments, R6is ethyl. In further embodiments, R6is propyl. In still other embodiments, R6is butyl. In yet further embodiments, R6is pentyl. In other embodiments, R6is hexyl.

[0051] According to the disclosure, R7is H, halo, C1-6alkyl, C1-6alkoxy, or cycloalkyl. In some embodiments, R7is H. In other embodiments, R7is halo, such as F, or Cl, or Br. In further embodiments, R7is C1-6alkyl, such as methyl, or ethyl, or propyl, or butyl, or pentyl, or hexyl. In still other embodiments, R7is C1-6alkoxy, such as methoxy, or ethoxy, or propoxy, or butoxy, or pentoxy, or hexoxy. In yet other embodiments, R7is cycloalkyl, such as cyclopropyl, or cyclobutyl, or cyclopentyl, or cyclohexyl. - 12 -4896-4398-0599.1120039.000146 | TYRA.037PCTe, . - 13 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0053] According to the disclosure, RAis H or C1-6alkyl. In some embodiments, RAis H. In other embodiments, RAis C1-6alkyl, such as methyl, or ethyl, or propyl, or butyl, or pentyl, or hexyl.

[0054] According to the disclosure, X2is CH or N. In some embodiments, X2is CH. In other embodiments, X2is N.

[0055] According to the disclosure, X3is bond or -NH-, provided that X2is CH when X3is -NH-. In some embodiments, X3is a bond. In other embodiments, X3is -NH-.

[0056] According to the disclosure, R8to R12are, independently, a bond to L, H, halo, C1-6alkyl, O-C1-6alkyl, CF3, or CN, wherein one of R8to R12is a bond to L. In some embodiments, at least one of R8to R12is H. In other embodiments, at least one of R8to R12is halo, such as Cl, or such as F, or such as Br. In further embodiments, at least one of R8to R12is C1-6alkyl, such as methyl, or ethyl, or propyl, or butyl, or pentyl, or hexyl. In yet other embodiments at least one of R8to R12is -OC1-6alkyl, such as -Omethyl, or -Oethyl, or - Opropyl, or -Obutyl, or -Opentyl, or -Ohexyl. In still further embodiments, at least one of R8to R12is CF3. In other embodiments, at least one of R8to R12is CN. In further embodiments, R8is a bond to L. In yet other embodiments, R9is a bond to L. In still further embodiments, R10is a bond to L. In other embodiments, R11is a bond to L. In further embodiments, R12is a bond to L.

[0057] According to the disclosure L is a bivalent linker bound at one valence through bond R3and bound at the other valence to a carbon atom of Z2. In some embodiments, L is -L2-Y2-L3-.

[0058] According to the disclosure, L2is a bond to Y2, -C(O)-, -C(O)NH-, -C(O)O-, -S(O)- or -SO2-. In some embodiments, L2is -C(O)-. In other embodiments, L2is -CONH-. In further embodiments, L2is -C(O)O-. In yet other embodiments, L2is -S(O)-. In still further embodiments, L2is -SO2-. In other embodiments, L2is a bond to Y2.

[0059] According to the disclosure, Y2is a bond to L3, -(C1-12alk)-, -(C2-12alken)-, - (C2-12alkyn)-, -(C1-12heteroalk)-, -C1-12alk-C(O)-, -C1-12alk-C(O)-NH-C1-12alk-C(O)-, -C(O)- C1-12alk-C(O)NH-, -NH-C2-12alkyn-, -O-(C0-12alk)-, -(C0-12alk)-O-, -O-(CH2CH2O)p-, -NH- (CH2CH2O)p-, -(CH2CH2O)p-, wherein p is 1-3, -optionally substituted cycloalk-, -optionally substituted heterocycloalk-, -optionally substituted aryl-, -optionally substituted heteroaryl-. In some embodiments, Y2is a bond to L3. In other embodiments, Y2is -(C1-12alk)-, such as - methyl-, or such as -ethyl-, or such as -propyl-, or such as -butyl-, or such as -pentyl-, or such - 14 -4896-4398-0599.1120039.000146 | TYRA.037PCT as -hexyl-, or such as -heptyl-, or such as -octyl-, or such as -nonyl-, or such as -decyl-. In further embodiments, Y2is -(C2-12alken)-, such as -ethenyl-, or such as -propenyl-, or such as -butenyl-, or such as -pentenyl-, or such as -hexenyl-, or such as -heptenyl-, or such as - octenyl-, or such as -nonenyl-, or such as -decenyl-. In other embodiments, Y2is -(C2- 12alkyn)-, such as -ethynyl-, or such as -propynyl-, or such as -butynyl-, or such as -pentynyl-, or such as -hexynyl-, or such as -heptynyl-, or such as -octynyl-, or such as -nonynyl-, or such as -decynyl-. In further embodiments, Y2is -(C1-8heteroalk)-. In yet other embodiments, Y2is -C1-12alk-C(O)-, such as -methyl-C(O)-, or such as -ethyl-C(O)-, or such as -propyl-C(O)-, or such as -butyl-C(O)-, or such as -pentyl-C(O)-, or such as -hexyl-C(O)-, or such as -heptyl- C(O)-, or such as -octyl-C(O)-. In still further embodiments, Y2is -C1-12alk-C(O)-NH-C1-12alk-C(O)-. In other embodiments, Y2is -optionally substituted cycloalk-, such as - optionally substituted cycloprop-, or -optionally substituted cyclobut-, or -optionally substituted cyclopent-, or -optionally substituted cyclohex-. In further embodiments, Y2is - optionally substituted heterocycloalk-, such as piperidinyl, piperazinyl, or azeteidinyl. In still other embodiments, Y2is optionally substituted aryl, such as phenyl. In yet other embodiments, Y2is optionally substituted heteroaryl. In still further embodiments, Y2is - NH-(C2-12alkyn)-, such as -NH-ethynyl-, or such as -NH-propynyl-, or such as -NH-butynyl-, or such as -NH-pentynyl-, or such as -NH-hexynyl-, or such as -NH-heptynyl-, or such as - NH-octynyl-, or such as -NH-nonynyl-, or such as -NH-decynyl-. In other embodiments, Y2is -C(O)-C1-12alk-C(O)NH-, such as -C(O)CH2C(O)NH-, or such as -C(O)CH2CH2C(O)NH-, or such as -C(O)-C3alk-C(O)NH-, or such as -C(O)-C4alk-C(O)NH-, or such as -C(O)-C5alk- C(O)NH-, or such as -C(O)-C6alk-C(O)NH-. In further embodiments, Y2is -O-(C0-12alk)-, such as -O-, or -O-methyl-, or such as -O-ethyl-, or such as -O-propyl-, or such as -O-butyl-, or such as -O-pentyl-, or such as -O-hexyl-, or such as -O-heptyl-, or such as -O-octyl-, or such as -O-nonyl-, or such as -O-decyl-. In yet other embodiments, Y2is -(C0-12alk)-O-, such as -methyl-O-, or such as -ethyl-O-, or such as -propyl-O-, or such as -butyl-O-, or such as - pentyl-O-, or such as -hexyl-O-, or such as -heptyl-O-, or such as -octyl-O-, or such as - nonyl-O-, or such as -decyl-O-. In still other embodiments, Y2is -O-(CH2CH2O)-, such as - O-(CH2CH2OCH2CH2O)-, or such as -O-(CH2CH2OCH2CH2OCH2CH2O)-. In yet further embodiments, Y2is -(CH2CH2O)p-, such as -(CH2CH2O)-, such as -(CH2CH2OCH2CH2O)-, or such as -(CH2CH2OCH2CH2OCH2CH2O)-. In further embodiments, Y2is -NH- - 15 -4896-4398-0599.1120039.000146 | TYRA.037PCT (CH2CH2O)p-, such as -NH-(CH2CH2O)-, such as -NH-(CH2CH2OCH2CH2O)-, or such as - NH-(CH2CH2OCH2CH2OCH2CH2O)-.

[0060] In some embodiments, Y2is -(C1-6alk)-NH-, (such as, for example, - (CH2C(CH3)2CH2)-NH-); -(CH2CH2O)p-(C1-6alk)-, wherein p is 1-4, (such as, for example, - (CH2CH2O)-(CH2CH2)-, -(CH2CH2O)2-(CH2CH2)-, -(CH2CH2O)3-(CH2CH2)-, or - (CH2CH2O)4-(CH2CH2)-); -(CH2CH2O)p-(C1-6alk)-NH-, wherein p is 1-4, (such as, for example, -(CH2CH2O)2-(CH2CH2)-NH- or -(CH2CH2O)3-(CH2CH2)-NH-); -optionally substituted heterocycloalk-C(O)-(CH2CH2O)p-(C1-6alk)-, wherein p is 1-4, (such as, for example, -piperidinyl-C(O)-(CH2CH2O)-(CH2CH2)-, -piperidinyl-C(O)-(CH2CH2O)2- (CH2CH2)-, -piperidinyl-C(O)-(CH2CH2O)3-(CH2CH2)-, or -piperidinyl-C(O)-(CH2CH2O)4- (CH2CH2)-); -(C1-6alk)-cycloalkyl-(C1-6alk)-NH-,(such as, for example, -CH2-cyclopropyl- CH2-NH-); or -C1-12alk-(optionally substituted heterocycloalk)-, (such as, for example, -CH2- piperazinyl-).

[0061] According to the disclosure, L3is a bond to Z2, -NH-, -O-, -(C1-12alk)-, -(C2-12alken)-, -(C2-12alkyn)-, -(C1-12heteroalk)-, -O-(C1-12alk)-C(O)-, -NH-(C1-12alk)-C(O)-, -C(O)- (C1-12alk)-NH-, -C1-12alk-C(O)-NH-C1-12alk-C(O)-, -C(O)-NH-(C1-12alk)-, -O-(C1-12alk)-, - C(O)-O-(C1-12alk)-, -C(O)-(C1-12alk)-, -C1-12alk-C(O)-, -optionally substituted cycloalk-, - optionally substituted heterocycloalk-, -optionally substituted spiroheterocycloalky-, - optionally substituted aryl-, -optionally substituted heteroaryl-, -C(O)C1-12alk-(optionally substituted heterocycloalk)-, -C(O)-C1-12alk-C(O)NH-, -NH-C2-12alkyn-, -O-(CH2CH2O)p-, - NH-(CH2CH2O)p-, -(CH2CH2O)p-, wherein p is 1-3. In some embodiments, L3is a bond to Z2. In other embodiments, L3is -NH-. In other embodiments, L3is -O-. In other embodiments, L3is -(C1-12alk)-, such as -methyl-, or such as -ethyl-, or such as -propyl-, or such as -butyl-, or such as -pentyl-, or such as -hexyl-, or such as -heptyl-, or such as -octyl-, or such as -nonyl-, or such as -decyl-. In further embodiments, L3is -(C2-12alken)-, such as - ethenyl-, or such as -propenyl-, or such as -butenyl-, or such as -pentenyl-, or such as - hexenyl-, or such as -heptenyl-, or such as -octenyl-, or such as -nonenyl-, or such as - decenyl-. In yet further embodiments, L3is -(C1-12heteroalk)-. In further embodiments, L3is -O-(C1-12alk)-C(O)-, such as -O-CH2-C(O)-, , or such as -O-CH2CH2-C(O)-, or such as -O- (C3alk)-C(O)-, or such as -O-(C4alk)-C(O)-, or such as -O-(C5alk)-C(O)-, or such as -O- (C6alk)-C(O)-. In yet other embodiments, L3is -NH-(C1-12alk)-C(O)-, such as -NH-CH2- C(O)-, , or such as -NH-CH2CH2-C(O)-, or such as -NH-(C3alk)-C(O)-, or such as -NH- - 16 -4896-4398-0599.1120039.000146 | TYRA.037PCT (C4alk)-C(O)-, or such as -NH-(C5alk)-C(O)-, or such as -NH-(C6alk)-C(O)-. In other embodiments, L3is -(C2-12alkyn)-, such as -ethynyl-, or such as -propynyl-, or such as - butynyl-, or such as -pentynyl-, or such as -hexynyl-, or such as -heptynyl-, or such as - octynyl-, or such as -nonynyl-, or such as -decynyl-.In further embodiments, L3is -C(O)-(C1- 12alk)-NH-, such as -C(O)-CH2-NH-, or such as -C(O)-CH2CH2-NH-, or such as -C(O)- (C3alk)-NH-, or such as -C(O)-(C4alkyl)-NH-, or such as -C(O)-(C5alk)-NH-, or such as - C(O)-(C6alk)-NH-, or such as -C(O)-(C7alk)-NH-, or such as -C(O)-(C8alk)-NH-. In yet further embodiments, L3is -C1-12alk-C(O)-NH-C1-12alk-C(O)-. In yet other embodiments, L3is -C(O)-NH-(C1-12alk)-, such as -C(O)-NH-CH2-, or such as -C(O)-NH-CH2CH2-, or such as -C(O)-NH-(C3alk)-, or such as -C(O)-NH-(C4alk)-, or such as -C(O)-NH-(C5alk)-, or such as -C(O)-NH-(C6alk)-, or such as -C(O)-NH-(C7alk)-, or such as -C(O)-NH-(C8alk)-. In still further embodiments, L3is -O-(C1-12alk)-, such as -O-CH2-, or such as -O-CH2CH2-, or such as -O-(C3alk)-, or such as -O-(C4alk)-, or such as -O-(C5alk)-, or such as -O-(C6alk)-, or such as -O-(C7alk)-, or such as -O-(C8alk)-. In other embodiments, L3is -C(O)-O-(C1-12alk)-, such as -C(O)-O-CH2-, or such as -C(O)-O-(CH2CH2)-, or such as -C(O)-O-(C3alk)-, or such as - C(O)-O-(C4alk)-, or such as-C(O) -O-(C5alk)-, or such as -C(O)-O-(C6alk)-. In further embodiments, L3is -C(O)-(C1-12alk)-, such as -C(O)-CH2-, or such as -C(O)-CH2CH2-, or such as -C(O)-(C3alk)-, or such as -C(O)-(C4alk)-, or such as -C(O)-(C5alk)-, or such as - C(O)-(C6alk)-. In still other embodiments, L3is -optionally substituted heterocycloalk-, such as optionally substituted piperazinyl, optionally substituted piperidinyl, or optionally substituted azetidinyl. In yet further embodiments, L3is optionally substituted spiroheterocycloalkyl, such as optionally substituted diazaspiroheptanyl, or such as diazaspiro[3.3]heptanyl. In other embodiments, L3is optionally substituted aryl, such as phenyl. In further embodiments, L3is optionally substituted heteroaryl. In still other embodiments, L3is -C(O)C1-12alk-(optionally substituted heterocycloalkyl)-, such as such as - C(O)CH2-(optionally substituted heterocycloalkyl)-, such as -C(O)CH2CH2-(optionally substituted heterocycloalkyl)-, or such as -C(O)C3alk-(optionally substituted heterocycloalkyl)-, or such as -C(O)C4alk-(optionally substituted heterocycloalkyl, or such as -C(O)C1-6alk-(optionally substituted heterocycloalkyl)-, or such as -C(O)C5alk-(optionally substituted heterocycloalkyl)-, or such as -C(O)C6alk-(optionally substituted heterocycloalkyl)-, or such as -C(O)CH2-optionally substituted piperidinyl-, -C(O)CH2- optionally substituted piperazinyl-, or -C(O)CH2-optionally substituted azetidinyl-. In yet - 17 -4896-4398-0599.1120039.000146 | TYRA.037PCT further embodiments, L3is -C(O)-C1-12alk-C(O)NH-, such as -C(O)-CH2-C(O)NH-, or such as -C(O)-CH2CH2-C(O)NH-, or such as -C(O)-C3alk-C(O)NH-, or such as -C(O)-C4alk- C(O)NH-, or such as -C(O)-C5alk-C(O)NH-, or such as -C(O)-C6alk-C(O)NH-. In other embodiments, L3is -NH-C2-12alkyn-, such as -NH-C≡C-, or such as -NH-C3alkyn-, or such as -NH-C4alkyn-, or such as -NH-C5alkyn-, or such as -NH-C6alkyn-. In further embodiments, L3is -O-(C1-12alk)-, such as -O-methyl-, or such as -O-ethyl-, or such as -O-propyl-, or such as -O-butyl-, or such as -O-pentyl-, or such as -O-hexyl-. In still other embodiments, L3is - (C1-12alk)-C(O)-, such as -methyl-C(O)-, or such as -ethyl-C(O)-, or such as -propyl-C(O)-, or such as -butyl-C(O)-, or such as -pentyl-C(O)-, or such as -hexyl-C(O)-. In yet further embodiments, L3is -O-(CH2CH2O)p-, such as -O-(CH2CH2O)-, or such as -O- (CH2CH2OCH2CH2O)-, or such as -O-(CH2CH2OCH2CH2OCH2CH2O)-. In other embodiments, L3is -NH-(CH2CH2O)p-, such as -NH-(CH2CH2O)-, or such as -NH- (CH2CH2OCH2CH2O)-, or such as -NH-(CH2CH2OCH2CH2OCH2CH2O)-. In further embodiments, L3is -(CH2CH2O)p-, such as -(CH2CH2O)-, or such as -(CH2CH2OCH2CH2O)- , or such as -(CH2CH2OCH2CH2OCH2CH2O)-. In yet other embodiments, L3is -cycloalk-, such as -cyclopropyl-, or such as -cyclobutyl-, or such as -cyclopentyl-, or such as - cyclohexyl-, or such as -cycloheptyl-, or such as -cyclooctyl-.

[0062] In some embodiments, L3is -(C1-C6alk)-C(O)-(optionally substituted heterocycloalky), (such as, for example, -CH2-C(O)-piperidinyl-, -CH2CH2-C(O)-piperidinyl- , or -CH2CH2CH2CH2CH2-C(O)-piperidinyl-); -C(O)-(optionally substituted heterocycloalk)-, (such as, for example, -C(O)-piperidinyl); -C(O)-(CH2CH2O)p-(C1-C6alk)-(optionally substituted heterocycloalk), wherein p is 1-4, (such as, for example, -C(O)-(CH2CH2O)2- (CH2CH2)-(piperazinyl) or -C(O)-(CH2CH2O)2-(CH2CH2)-(piperidinyl)); -C(O)-(C1-12alk)-O- , (such as, for example, -C(O)-CH2-O-); -(C1-12alk)-C(O)-NH-, (such as, for example, -CH2- C(O)-NH-); -C1-12alk-C(O)-(optionally substituted heterocycloalk)-, (such as, for example, - CH2-C(O)-piperidinyl- or -CH2-C(O)-piperazinyl-); -C1-12alk-(optionally substituted heterocycloalk)-, (such as, for example, -CH2-piperidinyl- or -CH2-piperazinyl-); -C(O)- (CH2CH2O)p-(C1-6alk)-, wherein p is 1-4, (such as, for example, -C(O)-(CH2CH2O)2- (CH2CH2)- or -C(O)-(CH2CH2O)3-(CH2CH2)-); or -(optionally substituted heterocycloalk)-, (such as, for example, pyridinyl or piperidinyl).

[0063] In certain embodiments, the compound is of formula II: - 18 -4896-4398-0599.1120039.000146 | TYRA.037PCTpharmaceutically acceptable salt thereof.

[0064] In other embodiments, the compound is formula III, wherein each Q1is, independently, N or CRC, wherein RCis H or C1-6alkyl, provided that at least one Q1is N:pharmaceutically acceptable salt thereof. In some embodiments, Q1is, independently, N. In other embodiments, Q1is CRC, wherein RCis H or C1-6alkyl. In further embodiments, RCis H. In yet other embodiments, RCis C1-6alkyl, such as methyl, or ethyl, or propyl, or butyl, or pentyl, or hexyl.

[0065] In further embodiments, the compound is of formula IV, wherein each Q1is, independently, N or CRC, wherein RCis H or C1-6alkyl, provided that at least one Q1is N: - 19 -4896-4398-0599.1120039.000146 | TYRA.037PCTpharmaceutically acceptable salt thereof. In some embodiments, Q1is, independently, N. In other embodiments, Q1is CRC, wherein RCis H or C1-6alkyl. In further embodiments, RCis H. In yet other embodiments, RCis C1-6alkyl, such as methyl, or ethyl, or propyl, or butyl, or pentyl, or hexyl.

[0066] In yet other embodiments, the compound is formula V, wherein each Q1is, independently, N or CRC, wherein RCis H or C1-6alkyl, provided that at least one Q1is N:pharmaceutically acceptable salt thereof. In some embodiments, Q1is, independently, N. In other embodiments, Q1is CRC, wherein RCis H or C1-6alkyl. In further embodiments, RCis H. In yet other embodiments, RCis C1-6alkyl, such as methyl, or ethyl, or propyl, or butyl, or pentyl, or hexyl.

[0067] In still further embodiments, the compound is of formula VI, wherein each Q1is, independently, N or CRC, wherein RCis H or C1-6alkyl, provided that at least one Q1is N: - 20 -4896-4398-0599.1120039.000146 | TYRA.037PCTpharmaceutically acceptable salt thereof. In some embodiments, Q1is, independently, N. In other embodiments, Q1is CRC, wherein RCis H or C1-6alkyl. In further embodiments, RCis H. In yet other embodiments, RCis C1-6alkyl, such as methyl, or ethyl, or propyl, or butyl, or pentyl, or hexyl.

[0068] In other embodiments, the compound is of formula VII, wherein each Q1is, independently, N or CRC, wherein RCis H or C1-6alkyl, provided that at least one Q1is N:pharmaceutically acceptable salt thereof. In some embodiments, Q1is, independently, N. In other embodiments, Q1is CRC, wherein RCis H or C1-6alkyl. In further embodiments, RCis H. In yet other embodiments, RCis C1-6alkyl, such as methyl, or ethyl, or propyl, or butyl, or pentyl, or hexyl.

[0069] In further embodiments, the compound is of formula VIII, wherein each Q1is, independently, N or CRC, wherein RCis H or C1-6alkyl, provided that at least one Q1is N: - 21 -4896-4398-0599.1120039.000146 | TYRA.037PCTpharmaceutically acceptable salt thereof. In some embodiments, Q1is, independently, N. In other embodiments, Q1is CRC, wherein RCis H or C1-6alkyl. In further embodiments, RCis H. In yet other embodiments, RCis C1-6alkyl, such as methyl, or ethyl, or propyl, or butyl, or pentyl, or hexyl.

[0070] In yet other embodiments, the compound is:- 22 -4896-4398-0599.11200399..0000114466 || TYRRAA.0.03377PPCCTT- -233- - 4896- -43988--0559999..11200399..0000114466 || TYRRAA.0.03377PPCCTT- -244- - 4896- -43988--0559999..11200399..0000114466 || TYRRAA.0.03377PPCCTT- -255- - 4896- -43988--0559999..11200399..0000114466 || TYRRAA.0.03377PPCCTT8- -266- - 4896- -43988--0559999..11200399..0000114466 || TYRRAA.0.03377PPCCTTO B O- -277- - 4896- -43988--0559999..11200399..0000114466 || TYRRAA.0.03377PPCCTT- -28 - - 4896- -43988--0559999..11200399..0000114466 || TYRRAA.0.03377PPCCTT- -29 - - 4896- -43988--0559999..11200399..0000114466 || TYRRAA.0.03377PPCCTT- -300- - 4896- -43988--0559999..11200399..0000114466 || TYRRAA.0.03377PPCCTT- 3] 31 - - 4896- -43988--0559999..1120039.000146 | TYRA.037PCT

[0071] In still further embodiments, the compound is:- 32 -4896-4398-0599.1120039.000146 | TYRA.037PCT- 33 -4896-4398-0599.1120039.000146 | TYRA.037PCT- 34 -4896-4398-0599.1120039.000146 | TYRA.037PCT- 35 -4896-4398-0599.1120039.000146 | TYRA.037PCT- 36 -4896-4398-0599.1120039.000146 | TYRA.037PCT- 37 -4896-4398-0599.1120039.000146 | TYRA.037PCT- 38 -4896-4398-0599.1120039.000146 | TYRA.037PCT di 1H 2, di 1H 2, di 1H 2,pentanamide 5-[4-[[6-[5-[5-[(1R)-1-(3,5- dichloro-4-pyridyl)ethoxy]- 1H-indazol-3-yl]-2-pyridyl]- 2,6-diazaspiro[3.3]heptan-2- yl]sulfonyl]-1-piperidyl]-N- [2-(2,6-dioxo-3-piperidyl)- 1,3-dioxo-isoindolin-5-yl]-5- oxo-pentanamide - 39 -4896-4398-0599.1120039.000146 | TYRA.037PCT- 40 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0072] In yet other embodiments, the compound is:- 41 -4896-4398-0599.1120039.000146 | TYRA.037PCT- 42 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0073] In some aspects, the disclosure is directed to the compounds shown in the Examples below, or pharmaceutically acceptable salts thereof. In some aspects, the disclosure is directed to the compound of any one of Examples 1-177, shown in the Examples section below, or a pharmaceutically acceptyable salt thereof.

[0074] References herein to formula (I) or subgenera thereof are meant to encompass the identified formula and any subgenera of those formula disclosed herein. For example, references to formula (I) also encompass subgenera (II)-(VIII).

[0075] Stereoisomers of compounds of formula (I) are also contemplated by the disclosure. Thus, the disclosure encompasses all stereoisomers and constitutional isomers of any compound disclosed or claimed herein, including all enantiomers and diastereomers, or mixtures thereof. - 43 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0076] Pharmaceutically acceptable salts and solvates of the compounds of formula (I) are also within the scope of the disclosure.

[0077] It is to be appreciated that certain features of the disclosure which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, unless obviously incompatible or specifically excluded, each individual embodiment is deemed to be combinable with any other embodiment(s) and such a combination is considered to be another embodiment. Conversely, various features of the disclosure that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination. While an embodiment may be described as part of a series of steps or part of a more general structure, each said step may also be considered an independent embodiment in itself, combinable with others. Pharmaceutical compositions and methods of administration

[0078] According to the disclosure, pharmaceutical compositions containing one or more compounds described herein are provided.

[0079] The subject pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of a compound of the disclosure as the active ingredient, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. In some embodiments, the pharmaceutical compositions contain a compound of the disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.

[0080] The subject pharmaceutical compositions can be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions. Where desired, the one or more compounds of the disclosure and other agent(s) may be mixed into a preparation or both components may be formulated into separate preparations to use them in combination separately or at the same time.

[0081] In some embodiments, the concentration of one or more compounds provided in the pharmaceutical compositions of the disclosure is less than about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, - 44 -4896-4398-0599.1120039.000146 | TYRA.037PCT about 19%, about 18%, about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about 0.01%, about 0.009%, about 0.008%, about 0.007%, about 0.006%, about 0.005%, about 0.004%, about 0.003%, about 0.002%, about 0.001%, about 0.0009%, about 0.0008%, about 0.0007%, about 0.0006%, about 0.0005%, about 0.0004%, about 0.0003%, about 0.0002%, or 0.0001% (or a number in the range defined by and including any two numbers above) w / w, w / v or v / v.

[0082] In some embodiments, the concentration of one or more compounds of the disclosure is greater than about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, about 19.75%, about 19.50%, about 19.25%, about 19%, about 18.75%, about 18.50%, about 18.25%, about 18%, about 17.75%, about 17.50%, about 17.25%, about 17%, about 16.75%, about 16.50%, about 16.25%, about 16%, about 15.75%, about 15.50%, about 15.25%, about 15%, about 14.75%, about 14.50%, 14.25%, about 14%, about 13.75%, about 13.50%, about 13.25%, about 13%, about 12.75%, about 12.50%, about 12.25%, about 12%, about 11.75%, about 11.50%, about 11.25% about 11%, about 10.75%, about 10.50%, about 10.25%, about 10%, about 9.75%, about 9.50%, about 9.25%, about 9%, about 8.75%, about 8.50%, about 8.25%, about 8%, about 7.75%, about 7.50%, about 7.25%, about 7%, about 6.75%, about 6.50%, about 6.25%, about 6%, about 5.75%, about 5.50%, about 5.25%, about 5%, about 4.75%, about 4.50%, about 4.25%, about 4%, about 3.75%, about 3.50%, about 3.25%, about 3%, about 2.75%, about 2.50%, about 2.25%, about 2%, about 1.75%, about 1.50%, about 1.25%, about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about 0.01%, 0.009%, about 0.008%, about 0.007%, about 0.006%, about 0.005%, about 0.004%, about 0.003%, about 0.002%, about 0.001%, about 0.0009%, about 0.0008%, about 0.0007%, 0.0006%, about 0.0005%, about 0.0004%, about 0.0003%, about 0.0002%, or about 0.0001% (or a number in the range defined by and including any two numbers above) w / w, w / v, or v / v.

[0083] In some embodiments, the concentration of one or more compounds of the disclosure is in the range from about 0.0001% to about 50%, about 0.001% to about 40%, - 45 -4896-4398-0599.1120039.000146 | TYRA.037PCT about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10% w / w, w / v or v / v.

[0084] In some embodiments, the concentration of one or more compounds of the disclosure is in the range from about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w / w, w / v or v / v.

[0085] In some embodiments, the amount of one or more compounds of the disclosure is equal to or less than about 10 g, about 9.5 g, about 9.0 g, about 8.5 g, about 8.0 g, about 7.5 g, about 7.0 g, about 6.5 g, about 6.0 g, about 5.5 g, about 5.0 g, about 4.5 g, 4.0 g, about 3.5 g, about 3.0 g, about 2.5 g, about 2.0 g, about 1.5 g, about 1.0 g, about 0.95 g, about 0.9 g, about 0.85 g, about 0.8 g, about 0.75 g, about 0.7 g, about 0.65 g, about 0.6 g, about 0.55 g, about 0.5 g, about 0.45 g, about 0.4 g, 0.35 g, about 0.3 g, about 0.25 g, about 0.2 g, about 0.15 g, about 0.1 g, about 0.09 g, about 0.08 g, about 0.07 g, about 0.06 g, about 0.05 g, about 0.04 g, about 0.03 g, about 0.02 g, about 0.01 g, about 0.009 g, about 0.008 g, about 0.007 g, about 0.006 g, about 0.005 g, about 0.004 g, about 0.003 g, about 0.002 g, about 0.001 g, about 0.0009 g, about 0.0008 g, about 0.0007 g, about 0.0006 g, about 0.0005 g, about 0.0004 g, 0.0003 g, about 0.0002 g, or about 0.0001 g (or a number in the range defined by and including any two numbers above).

[0086] In some embodiments, the amount of one or more compounds of the disclosure is more than about 0.0001 g, about 0.0002 g, about 0.0003 g, about 0.0004 g, about 0.0005 g, about 0.0006 g, about 0.0007 g, about 0.0008 g, about 0.0009 g, about 0.001 g, about 0.0015 g, about 0.002 g, about 0.0025 g, about 0.003 g, about 0.0035 g, about 0.004 g, about 0.0045 g, about 0.005 g, about 0.0055 g, about 0.006 g, about 0.0065 g, about 0.007 g, about 0.0075 g, about 0.008 g, about 0.0085 g, about 0.009 g, about 0.0095 g, about 0.01 g, about 0.015 g, about 0.02 g, about 0.025 g, about 0.03 g, about 0.035 g, about 0.04 g, about 0.045 g, about 0.05 g, about 0.055 g, about 0.06 g, about 0.065 g, about 0.07 g, about 0.075 g, about 0.08 g, about 0.085 g, about 0.09 g, about 0.095 g, about 0.1 g, about 0.15 g, about 0.2 - 46 -4896-4398-0599.1120039.000146 | TYRA.037PCT g, about 0.25 g, about 0.3 g, about 0.35 g, about 0.4 g, about 0.45 g, about 0.5 g, about 0.55 g, about 0.6 g, about 0.65 g, about 0.7 g, about 0.75 g, about 0.8 g, about 0.85 g, about 0.9 g, about 0.95 g, about 1 g, about 1.5 g, about 2 g, about 2.5, about 3 g, about 3.5, about 4 g, about 4.5 g, about 5 g, 5.5 g, about 6 g, about 6.5 g, about 7 g, about 7.5g, about 8 g, about 8.5 g, about 9 g, about 9.5 g, or about 10 g (or a number in the range defined by and including any two numbers above).

[0087] In some embodiments, the amount of one or more compounds of the disclosure is in the range of about 0.0001 to about 10 g, about 0.0005 to about 9 g, about 0.001 to about 8 g, about 0.005 to about 7 g, about 0.01 to about 6 g, about 0.05 to about 5 g, about 0.1 to about 4 g, about 0.5 to about 4 g, or about 1 to about 3 g.

[0088] In some embodiments, the compounds according to the disclosure are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from about 0.01 to about 1000 mg, from about 0.5 to about 100 mg, from about 1 to about 50 mg per day, and about from 5 to about 40 mg per day are examples of dosages that may be used. An exemplary dosage is about 10 to about 30 mg per day. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.

[0089] Unless otherwise noted, the amounts of the compounds described herein are set forth on a free base basis. That is, the amounts indicate that amount of the compound administered, exclusive of, for example, solvent (such as in solvates) or counterions (such as in pharmaceutically acceptable salts).

[0090] Described below are non-limiting exemplary pharmaceutical compositions and methods for preparing the same. Pharmaceutical compositions for oral administration.

[0091] In some embodiments, the disclosure provides a pharmaceutical composition for oral administration containing a compound of the disclosure, and a pharmaceutical excipient suitable for oral administration.

[0092] In some embodiments, the disclosure provides a solid pharmaceutical composition for oral administration containing: (i) an effective amount of a compound of the disclosure; optionally (ii) an effective amount of a second agent; and (iii) a pharmaceutical - 47 -4896-4398-0599.1120039.000146 | TYRA.037PCT excipient suitable for oral administration. In some embodiments, the composition further contains: (iv) an effective amount of a third agent.

[0093] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption. Pharmaceutical compositions of the disclosure suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and / or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0094] This disclosure further encompasses anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, since water can facilitate the degradation of some compounds. For example, water may be added (e.g., about 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. Anhydrous pharmaceutical compositions and dosage forms of the disclosure can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms of the disclosure which contain lactose can be made anhydrous if substantial contact with moisture and / or humidity during manufacturing, packaging, and / or storage is expected. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions may be packaged using materials known to prevent - 48 -4896-4398-0599.1120039.000146 | TYRA.037PCT exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.

[0095] An active ingredient can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the compositions for an oral dosage form, any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose. For example, suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.

[0096] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.

[0097] Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

[0098] Disintegrants may be used in the compositions of the disclosure to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which may disintegrate in the bottle. Too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be - 49 -4896-4398-0599.1120039.000146 | TYRA.037PCT used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the disclosure include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.

[0099] Lubricants which can be used to form pharmaceutical compositions and dosage forms of the disclosure include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof. A lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.

[0100] When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and / or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

[0101] The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil. - 50 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0102] Surfactant which can be used to form pharmaceutical compositions and dosage forms of the disclosure include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.

[0103] A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (" HLB" value). Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions.

[0104] Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.

[0105] Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acyl lactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di- glycerides; and mixtures thereof.

[0106] Within the aforementioned group, ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; - 51 -4896-4398-0599.1120039.000146 | TYRA.037PCT succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

[0107] Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG- phosphatidylethanolamine, PVP -phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono / diacetylated tartaric acid esters of mono / diglycerides, citric acid esters of mono / diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof.

[0108] Hydrophilic non-ionic surfactants may include, but are not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a polyol with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.

[0109] Other hydrophilic-non-ionic surfactants include, without limitation, PEG- 10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, - 52 -4896-4398-0599.1120039.000146 | TYRA.037PCT PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate / caprylate glycerides, PEG-8 caprate / caprylate glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-l0-oleate, Tween 40, Tween 60, sucrose monostearate, sucrose mono laurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers.

[0110] Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins / vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0111] In one embodiment, the composition may include a solubilizer to ensure good solubilization and / or dissolution of the compound of the disclosure and to minimize precipitation of the compound of the disclosure. This can be especially important for compositions for non-oral use, e.g., compositions for injection. A solubilizer may also be added to increase the solubility of the hydrophilic drug and / or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[0112] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, - 53 -4896-4398-0599.1120039.000146 | TYRA.037PCT ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG ; amides and other nitrogen-containing compounds such as 2- pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactone and isomers thereof, β-butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and water.

[0113] Mixtures of solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N- methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.

[0114] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example to maximize the concentration of the drug, with excess solubilizer removed prior to providing the composition to a subject using conventional techniques, such as distillation or evaporation. Thus, if present, the solubilizer can be in a weight ratio of about 10%, about 25%, about 50%), about 100%, or up to about 200%> by weight, based on the combined weight of the drug, and other excipients. If desired, very small amounts of solubilizer may also be used, such as about 5%>, about 2%>, about 1%) or even less. Typically, the - 54 -4896-4398-0599.1120039.000146 | TYRA.037PCT solubilizer may be present in an amount of about 1%> to about 100%, more typically about 5%> to about 25%> by weight.

[0115] The composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0116] In addition, an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable are bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para- bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. Salts of polyprotic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.

[0117] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic - 55 -4896-4398-0599.1120039.000146 | TYRA.037PCT acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the like. Pharmaceutical compositions for injection.

[0118] In some embodiments, the disclosure provides a pharmaceutical composition for injection containing a compound of the disclosure and a pharmaceutical excipient suitable for injection. Components and amounts of agents in the compositions are as described herein.

[0119] The forms in which the novel compositions of the disclosure may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[0120] Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0121] Sterile injectable solutions are prepared by incorporating the compound of the disclosure in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, certain desirable methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0122] Pharmaceutical compositions for topical (e.g. transdermal) delivery. - 56 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0123] In some embodiments, the disclosure provides a pharmaceutical composition for transdermal delivery containing a compound of the disclosure and a pharmaceutical excipient suitable for transdermal delivery.

[0124] Compositions of the disclosure can be formulated into preparations in solid, semisolid, or liquid forms suitable for local or topical administration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO)- based solutions. In general, carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients. In contrast, a solution formulation may provide more immediate exposure of the active ingredient to the chosen area.

[0125] The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability barrier of the skin. There are many of these penetration-enhancing molecules known to those trained in the art of topical formulation.

[0126] Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[0127] Another exemplary formulation for use in the methods of the disclosure employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of a compound of the disclosure in controlled amounts, either with or without another agent. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos.5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Pharmaceutical compositions for inhalation. - 57 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0128] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner. Other pharmaceutical compositions.

[0129] Pharmaceutical compositions may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical compositions are well-known in the art. See, e.g., Anderson, Knoben, Troutman, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001 ; Remington’s Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all of which are incorporated by reference herein in their entirety.

[0130] Administration of the compounds or pharmaceutical composition of the disclosure can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g. transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. Compounds can also be administered intraadiposally or intrathecally. - 58 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0131] The amount of the compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g / day, preferably about 0.05 to about 2.5 g / day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g. by dividing such larger doses into several small doses for administration throughout the day.

[0132] In some embodiments, a compound of the disclosure is administered in a single dose.

[0133] Typically, such administration will be by injection, e.g., intravenous injection, in order to introduce the agent quickly. However, other routes may be used as appropriate. A single dose of a compound of the disclosure may also be used for treatment of an acute condition.

[0134] In some embodiments, a compound of the disclosure is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be about once a month, once every two weeks, once a week, or once every other day. In another embodiment a compound of the disclosure and another agent are administered together about once per day to about 6 times per day. In another embodiment the administration of a compound of the disclosure and an agent continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.

[0135] Administration of the compounds of the disclosure may continue as long as necessary. In some embodiments, a compound of the disclosure is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a compound of the disclosure is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound of the disclosure is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects. - 59 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0136] An effective amount of a compound of the disclosure may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra- arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0137] The compositions of the disclosure may also be delivered via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer. Such a method of administration may, for example, aid in the prevention or amelioration of restenosis following procedures such as balloon angioplasty. Without being bound by theory, compounds of the disclosure may slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall which contribute to restenosis. A compound of the disclosure may be administered, for example, by local delivery from the struts of a stent, from a stent graft, from grafts, or from the cover or sheath of a stent. In some embodiments, a compound of the disclosure is admixed with a matrix. Such a matrix may be a polymeric matrix, and may serve to bond the compound to the stent. Polymeric matrices suitable for such use, include, for example, lactone-based polyesters or copolyesters such as polylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester) copolymers (e.g. PEO-PLLA); polydimethylsiloxane, poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g. polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone), fluorinated polymers such as polytetrafluoroethylene and cellulose esters. Suitable matrices may be nondegrading or may degrade with time, releasing the compound or compounds. Compounds of the disclosure may be applied to the surface of the stent by various methods such as dip / spin coating, spray coating, dip-coating, and / or brush-coating. The compounds may be applied in a solvent and the solvent may be allowed to evaporate, thus forming a layer of compound onto the stent. Alternatively, the compound may be located in the body of the stent or graft, for example in microchannels or micropores. When implanted, the compound diffuses out of the body of the stent to contact the arterial wall. Such stents may be prepared by dipping a stent manufactured to contain such micropores or microchannels into a solution of the compound of the disclosure in a suitable solvent, followed by evaporation of the solvent. Excess drug on the surface of the stent may be removed via an additional brief solvent wash. In yet other embodiments, compounds of the disclosure may be covalently linked to a stent or - 60 -4896-4398-0599.1120039.000146 | TYRA.037PCT graft. A covalent linker may be used which degrades in vivo, leading to the release of the compound of the disclosure. Any bio-labile linkage may be used for such a purpose, such as ester, amide or anhydride linkages. Compounds of the disclosure may additionally be administered intravascularly from a balloon used during angioplasty. Extravascular administration of the compounds via the pericard or via advential application of formulations of the disclosure may also be performed to decrease restenosis.

[0138] A variety of stent devices which may be used as described are disclosed, for example, in the following references, all of which are hereby incorporated by reference: U.S. Pat. No.5451233; U.S. Pat. No.5040548; U.S. Pat. No.5061273; U.S. Pat. No. 5496346; U.S. Pat. No.5292331; U.S. Pat. No.5674278; U.S. Pat. No.3657744; U.S. Pat. No.4739762; U.S. Pat. No.5195984; U.S. Pat. No.5292331; U.S. Pat. No.5674278; U.S. Pat. No.5879382; U.S. Pat. No.6344053.

[0139] The compounds of the disclosure may be administered in dosages. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Dosing for a compound of the disclosure may be found by routine experimentation in light of the instant disclosure.

[0140] When a compound of the disclosure is administered in a composition that comprises one or more agents, and the agent has a shorter half-life than the compound of the disclosure unit dose forms of the agent and the compound of the disclosure may be adjusted accordingly.

[0141] The subject pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the disclosure as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

[0142] Exemplary parenteral administration forms include solutions or suspensions of active compound in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired. - 61 -4896-4398-0599.1120039.000146 | TYRA.037PCT Methods of use

[0143] The FGFR receptors (FGFRl, FGFR2, FGFR3, and FGFR4) share several structural features in common, including three extracellular immunoglobulin-like (Ig) domains, a hydrophobic transmembrane domain, and an intracellular tyrosine kinase domain split by a kinase insert domain, followed by a cytoplasmic c-terminal tail (Johnson\, Adv. Cancer Res.60:1-40, 1993; and Wilkie, Curr. Biol.5:500-507, 1995). In FGFRl, the kinase insert domain spans positions 582 to 595 of the alpha Al isoform of FGFRl. In FGFR2, the kinase insert domain spans positions 585 to 598 of the FGFR2 Ille isoform. In FGFR3, the kinase insert domain spans positions 576 to 589 of the FGFR3 Ille isoform. In FGFR4, the kinase insert domain spans positions 571 to 584 of FGFR4 isoform 1. The c-terminal tail of FGFRs begins following the end of the tyrosine kinase domain and extends to the c-terminus of the protein. Several isoforms of each FGFR have been identified and are the result of alternative splicing of their mRNAs (Johnson, Mol. Cell. Biol. 11:4627-4634, 1995; and Chellaiah, J. Biol. Chem.269:11620-11627, 1994).

[0144] A few of the receptor variants that result from this alternative splicing have different ligand binding specificities and affinities (Zimmer, J. Biol. Chem.268:7899-7903, 1993; Cheon, Proc. Natl. Acad. Sci. U.S.A.91:989-993, 1994; and Miki, Proc. Natl. Acad. Sci. U.S.A.89:246-250, 1992). Protein sequences for FGFR proteins and nucleic acids encoding FGFR proteins are known in the art. Signaling by FGFRs regulates key biological processes including cell proliferation, survival, migration, and differentiation. Dysregulation of a FGFR gene, a FGFR protein, or expression or activity, or level of the same, has been associated with many types of cancer. For example, dysregulation of FGFRs can occur by multiple mechanisms, such as FGFR gene overexpression, FGFR gene amplification, activating mutations (e.g., point mutations or truncations), and chromosomal rearrangements that lead to FGFR fusion proteins. Dysregulation of a FGFR gene, a FGFR protein, or expression or activity, or level of the same, can result in (or cause in part) the development of a variety of different FGFR-associated cancers.

[0145] FGFR fusion proteins are known in the art. See, e.g., Baroy, PloS One; 11(9):e0163859, 2016; Ren, Int. J. Cancer, 139(4):836-40, 2016; Marchwicka, Cell Biosci., 6:7, 2016; PCT Patent Application Publication No. WO-2014 / 071419A2; U.S. Patent Application Publication No.2015 / 0366866Al; PCT Patent Application Publication No. WO- 2016 / 084883Al; PCT Patent Application Publication No. WO-2016 / 030509Al; PCT Patent - 62 -4896-4398-0599.1120039.000146 | TYRA.037PCT Application Publication No. WO-2015 / 150900A2; PCT Patent Application Publication No. WO-2015 / 120094A2; Kasaian, BMC Cancer., 15:984, 2015; Vakil, Neuro-Oncology, 18: Supplement 3, pp. iii93. Abstract Number: LG-64, 17thInternational Symposium on Pediatric Neuro-Oncology, Liverpool, United Kingdom, 2016; Astsaturov, Journal of Clinical Oncology, 34: Supplement 15, Abstract Number: 11504, 2016 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL; Heinrich, Journal of Clinical Oncology, 34:Supplement 15, Abstract Number: 11012, 2016 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL; Hall, Molecular Cancer Therapeutics, Vol.14, No.12, Supp.2, Abstract Number: B151, AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, 2015; Reuther, Journal of Molecular Diagnostics, Vol.17, No.6, pp.813, Abstract Number: ST02, 2015 Annual Meeting of the Association for Molecular Pathology, Austin, TX; Moeini, Clin. Cancer. Res., 22(2):291-300, 2016; Schrock, J Thorac. Oncol., 13(9):1312, 2018; Pekmezci, Acta Neuropathol. Commun.6(1):47; Lowery, Clin Cancer Res., 24(17):4154, 2018; Ryland, J Clin Pathol., 71(10):895, 2018; J Neuropathol. Exp Neural 77(6):437-442, 2018; Wu, BMC Cancer 18(1):343, 2018; Shibata, Cancer Sci 109(5):1282-1291, 2018; Papdopoulos, Br J Cancer, 1117(11):1592-1599, 2017; Hall, PLoS One, 11(9):e1062594, 2016; Johnson, Oncologist, 22(12):1478-1490, 2017; Yang, Am J Hum Genet, 98(5):843-856, 2016; U.S. Patent Application Publication No.2013 / 009621; Babina and Turner, Nat Rev Cancer 17(5):318-332, 2017; Ryland, J Clin Patho., 2018 May 14, 71(10):895; Kumar, Am J Clin Pathol.143(5):738-748, 2015; Grand, Genes Chromosomes Cancer, 40(1):78-83, 2004; Reeser, J Mol. Diagn, 19(5):682-696, 2017; Basturk, Mod Pathol, 30(12):1760-1772, 2017; Wang, Cancer 123(20):3916-3924, 2017; Kim, Oncotarget, 8(9):15014-15022, 2017; Busse, Genes Chromosomes Cancer, 56(10):730-749, 2017; Shi, J Transl Med., 14(1):339, 2016, each of which is incorporated by reference herein.

[0146] FGFR point mutations are known in the art. See, e.g., UniParc entry UPI00000534B8; UniParc entry UPI000000lCOF; UniParc entry UPI000002A99A; UniParc entry UPI000012A72A; UniParc entry UPI000059D1C2; UniParc entry UPI000002A9AC; UniParc entry UPI000012A72C; UniParc entry UPI000012A72D; UniParc entry UPI000013EOB8; UniParc entry UPI0001CE06A3; Gen bank entry BAD92868.l; Ang, Diagn. Mol. Pathol. Feb 24, 2014; U.S. Patent Application Publication No.2011 / 0008347; Gallo, Cytokine Growth Factor Rev.26:425-449, 2015; Davies, J. Cancer Res.65:7591, - 63 -4896-4398-0599.1120039.000146 | TYRA.037PCT 2005; Kelleher, Carcinogenesis 34:2198, 2013; Cazier, Nat. Commun.5:3756, 2014; Liu, Genet. Mol. Res.13:1109, 2014; Trudel, Blood 107:4039, 2006; Gallo, Cytokine Growth Factor Rev.26:425, 2015; Liao, Cancer Res.73:5195-5205, 2013; Martincorena, Science, 348:880, 2015; U.S. Patent Application Publication No.2016 / 0235744; U.S. Patent No. 9254288; U.S. Patent No.9267176; U.S. Patent Application Publication No.2016 / 0215350; European Patent Application Publication No.3023101; PCT Patent Application Publication No. WO-2016 / 105503; Rivera, Acta. Neuropathol., 131(6):847-63, 2016; Lo Iacono, Oncotarget., 7(12):14394-404, 2016; Deeken, Journal of Clinical Oncology, 34: Supplement 15, pp. iii93. Abstract Number: el 7520, 2016 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL; Sullivan, Journal of Clinical Oncology, 34: Supplement 15, pp. iii93. Abstract Number: 11596, 2016 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL; Nguyen, Molecular Cancer Therapeutics, Vol.14, No.12, Supp.2, Abstract Number: C199, AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, 2015; Li, Hum. Pathol., 55:143-50, 2016; European Patent No. 2203449; Yoza, Genes Cells., (10):1049-1058, 2016; U.S. Patent No.9,254,288; European Patent Application Publication No.3023101; PCT Application Publication No. WO- 2015 / 099127Al; European Patent No.2203449; Yoza, Genes Cells., (10):1049-1058, 2016; Bunney, EBioMedicine, 2(3):194-204, 2015; Byron, Neoplasia, 15(8):975-88, 2013; European Patent Application Publication No.3023101; PCT Application Publication No. WO-2015 / 099127Al; Thussbas, J. Clin. Oncol., 24(23):3747-55, 2006; Chell, Oncogene, 32(25):3059-70, 2013; Tanizaki, Cancer Res.75(15):3149-3146, 2015; Yang, EBioMedicine, 2018, 35:198; Jakobsen, Oncotarget 9(40):26195-26208, 2018; Stone, Acta Neuropathol. 135(1):115-129, 2017; Pekmezci, Acta Neuropathol. Commun.6(1):47, 2018; De Mattos- Arruda, Oncotarget 9(29):20617-20630, 2018; Oliveira, J Exp Clin Cancer Res 37(1):84, 2018; Cha, Mol. Oncol.12(7):993-1003, 2018; Ikeda, Oncologist, 23(5):586-593, 2018; Pelaez-Garda, PLoS One, 8(5):e63695, 2013; Shimada, Oncotarget, 8(55):93567-93579, 2017; Welander, World J Surg, 42(2):482-489, 2018; Chandrani, Ann Oncol, 28(3):597-603, 2017; Dalin, Nat Commun, 8(1):1197, 2017; Taurin, Intl Gynecol. Cancer, 28(1):152-160, 2018; Haugh, J Invest Dermatol 138(2):384-393, 2018; Babina and Turner, Nat Rev Cancer 17(5):318-332, 2017; Greenman, Nature 446(7132):153-158, 2007; Helsten, Clin Cancer Res, 22(1):259-267, 2016; Kim, BMC Urol, 18:68, 2018; Goyal, Cancer Discov, 7(3):252- 263, 2017; Premov, Oncogene, 36(22):3168-3177, 2017; Geelvink, Int J Mol. Sci.19(9): - 64 -4896-4398-0599.1120039.000146 | TYRA.037PCT pii:E2548, 2018; Lee, Exp Ther Med.16(2):1343-1349, 2018; Kas, Cancer Res, 78(19):5668- 5679, 2018; Chesi, Blood, 97(3):729-736, 2001. Note that the deletion of FGFR3 isoform Ille residues 795-808 also deletes the stop codon, elongating the protein by 99 amino acids (ATGPQQCEGSLAAHPAAGAQPLPGMRLSADGETATQSFGLCVCVCVCVCVCTSACACVR AHLASRCRGTLGVPAA VQRSPDWCCSTEGPLFWGDPVQNVSGPTRWDPVGQGAGPDMARPLPLHHGTSQGALG PSHTQS); Ge, Am J Cancer Res.7(7):1540-1553, 2017; Jiao, Nat Genet, 45(12):1470-1473, 2013; Jusakul, Cancer Discov.7(10):1116-1135, 2017; Guyard, Respir Res., 18(1):120, 2018; Paik, Clin Cancer Res., 23(18):5366-5373, 2017; Roy, Mod Pathol., 30(8):1133-1143, 2017; Chakrabarty, Br J Cancer, 117(1):136-143, 2017; Hoang, Sci Transl Med., 5(197):197ra102; Kim, Ann Oncol., 28(6):1250-1259, each of which is incorporated by reference herein.

[0147] Compounds of the disclosure have been found to inhibit FGFRl, FGFR2, FGFR3, and / or FGFR4 and are therefore believed to be useful for treating diseases and disorders which can be treated with an inhibitor of FGFRl, FGFR2, FGFR3 and / or FGFR4. For example, compounds of the disclosure can be useful in treating FGFR-associated diseases and disorders, e.g., proliferative disorders such as cancers, including hematological cancers and solid tumor, and angiogenesis-related disorders. Compounds of the disclosure may also be useful in treating disorders arising from autosomal dominant mutations in FGFR, e.g., FGFR3, including, for example, developmental disorders. Developmental disorders to be treated with compounds of the disclosure include Achondroplasia (Ach) and related chondrodysplasia syndromes, including Hypochondroplasia (Hch), Severe Achondroplasia with Developmental Delay and Acanthosis Nigricans (SADDAN), and Thanatophoric dysplasia (TD). Compounds of the disclosure may also be useful in Double dominant ACH. Compounds of the disclosure may also be useful in Craniosynostosis, e.g., Crouzon syndrome with acanthosis nigricans and Meunke syndrome. Compounds of the disclosure may also be useful in other genetic short stature conditions, e.g., Leri-Weill dyschondrosteosis, Turner syndrome, Osteogenesis imperfecta, Mucopolysaccaridoses IVA, Mucopolysaccaridoses VI, and Laron syndrome (growth hormone insensitivity). Compounds of the disclosure may also be useful in pediatric short stature conditions, e.g., Idiopathic short stature and Severe idiopathic short stature. Compounds of the disclosure may also be useful in Camptodactyly, Tall Stature, and Hearing Loss (CATSHL). - 65 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0148] Non-limiting examples of FGFR-associated diseases and disorders include Acanthosis nigricans, Achondroplasia, Apert syndrome, Beare-Stevenson syndrome (BSS), Camptodactyly, tall stature, and hearing loss syndrome (CATSHL) syndrome, cleft lip and palate, congenital heart disease (e.g., associated with ambiguous genitalia), craniosynostosis, Crouzon syndrome, ectrodactyly, encephalocraniocutaneous lipomatosis, Hartsfield syndrome, hypochondroplasia, hypogonadoropic hypogonadism (e.g., hypogonadotropic hypogonadism 2 with or without anosmia, Kallman syndrome), ichthyosis vulgaris and / or atopic dermatitis, Jackson-Weiss syndrome, lethal pulmonary acinar dysplasia, microphthalmia, Muenke coronal craniosynostosis, osteoglophonic dysplasia, Pfeiffer syndrome, seborrheic keratosis, syndactyly, thanatophoric dysplasia (e.g., type I or type II), trigonocephaly 1 (also called metopic craniosynostosis), and tumor-induced osteomalacia.

[0149] Non-limiting examples of FGFRl associated diseases and disorders include congenital heart disease (e.g., associated with ambiguous genitalia), craniosynostosis, encephalocraniocutaneous lipomatosis, Hartsfield syndrome, hypogonadoropic hypogonadism (e.g., hypogonadotropic hypogonadism 2 with or without anosmia, Kallman syndrome), ichthyosis vulgaris and / or atopic dermatitis, Jackson-Weiss syndrome, osteoglophonic dysplasia, Pfeiffer syndrome, trigonocephaly 1 (also called metopic craniosynostosisand tumor-induced osteomalacia, Crouzon syndrome with acanthosis nigricans, Meunke syndrome, Leri-Weill dyschondrosteosis, Turner syndrome, Osteogenesis imperfecta, Mucopolysaccaridoses IVA, Mucopolysaccaridoses VI, Laron syndrome, Idiopathic short stature, Severe idiopathic short stature, and Camptodactyly, Tall Stature, and Hearing Loss (CATSHL).

[0150] Non-limiting examples of FGFR2-associated diseases and disorders include Apert syndrome, Beare-Stevenson syndrome (BSS), Crouzon syndrome, ectrodactyly, Jackson-Weiss syndrome, lethal pulmonary acinar dysplasia, Pfeiffer syndrome, and syndactyly. Non-limiting examples of FGFR3-associated diseases and disorders include acanthosis nigricans, achondroplasia, Camptodactyly, tall stature, and hearing loss syndrome (CATSHL) syndrome, cleft lip and palate, craniosynostosis, hypochondroplasia, microphthalmia, Muenke coronal craniosynostosis, seborrheic keratosis, and thanatophoric dysplasia (e.g., type I or type II). See also, See UniParc entry UPI00000534B8; UniParc entry UPI000000lCOF;Uni Pare entry UPI000002A99A;UniParc entry UPI000012A72A;Yong-Xing, Hum. Mol. Genet.9(13):2001-2008, 2000; Eeva-Maria - 66 -4896-4398-0599.1120039.000146 | TYRA.037PCT Laitinen, PLoS One 7(6):e39450, 2012; Hart, Oncogene 19(29):3309-3320, 2000; Shiang, Cell 76:335-342, 1994; Rosseau, Nature 371:252-254, 1994; Tavormina, Nature Genet. 9:321-328, 1995; Bellus, Nature Genet.10:357-359, 1995; Muenke, Nature Genet.8:269- 274, 1994; Rutland, Nature Genet.9:173-176, 1995; Reardon, Nature Genet.8:98-103, 1994; Wilkie, Nature Genet.9:165-172, 1995; Jabs, Nature Genet.8:275-279, 1994; Japanese Patent No.05868992; Ye, Plast. Reconstr. Surg., 137(3):952-61, 2016; U.S. Patent No. 9447098; Bellus, Am. J. Med. Genet.85(1):53-65, 1999; PCT Patent Application Publication No. WO-2016139227; Australian Patent Application Publication No. AU2014362227Al; Chinese Patent No.102741256; Ohishi, Am. J. Med. Genet. A., 173(1):157, 2016; Nagahara, Clin. Pediatr. Endocrinol., 25(3): 103-106, 2016; Hibberd, Am. J. Med. Genet. A., 170(12):3215, 2016; Dias, Exp. Mol. Pathol., 101(1):116-23, 2016; Lin, Mol. Med. Rep., 14(3):1941-6, 2016; Barnett, Hum. Mutat., 37(9):955-63, 2016; Krstevska-Konstantinova, Med. Arch., 70(2):148-50, 2016; Kuentz, Br. J. Dermatol., 176(1):204, 2016; Ron, Am. J. Case Rep., 15;17:254-8, 2016; Fernandes, Am. J. Med. Genet. A., 170(6):1532-7, 2016; Lindy, Am. J. Med. Genet. A., 170(6):1573-9, 2016; Bennett, Am. J. Hum. Genet., 98(3):579-87, 2016; lchiyama, J. Eur. Acad. Dermatol. Venereal., 30(3):442-5, 2016; Zhao, Int. J. Clin. Exp. Med., 8(10):19241-9, 2015; Hasegawa, Am. J. Med. Genet. A., 170A(5):1370-2, 2016; Legeai-Mallet, Endocr. Dev., 30:98-105, 2016; Takagi, Am. J. Med. Genet. A., 167A(11):2851-4, 2015; Goncalves, Fertil. Steril., 104(5):1261-7.el, 2015; Miller, Journal of Clinical Oncology, 34:Supp. Supplement 15, pp. iii93. Abstract Number: e22500, 2016 Annual Meeting of the American Society of Clinical Oncology, Chicago, IL; Sarabipour, J. Mol. Biol., 428(20):3903-3910, 2016; Escobar, Am. J. Med. Genet. A., 170(7):1908-11, 2016; Mazen, Sex Dev., 10(1):16-22, 2016; Taylan, J Allergy Clin lmmunol, 136(2):507-9, 2015; Kant, EuroJourn Endocrinol, 172(6):763-770, 2015; Gonzalez-Del Angel, Am J Med Genet A, 176(1):161-166, 2018; Lei and Deng, Int J Biol Sci 13(9):1163:1171, 2017; Lajeunie, Eur J Hum Genet, 14(3):289-298, 2006; Karadimas, Prenat Diagn, 26(3):258-261, 2006; lbrahimi, Hum Mol. Genet 13(19):2313-2324, 2004; Trarbach, J Clin Endocrinol Metab., 91(10):4006-4012, 2006; Dode, Nat Genet, 33(4):463- 465, 2003, each of which is incorporated by reference herein.

[0151] The term "angiogenesis-related disorder" means a disease characterized in part by an increased number or size of blood vessels in a tissue in a subject or patient, as compared to a similar tissue from a subject not having the disease. Non-limiting examples of - 67 -4896-4398-0599.1120039.000146 | TYRA.037PCT angiogenesis-related disorders include: cancer (e.g., any of the exemplary cancers described herein, such as prostate cancer, lung cancer, breast cancer, bladder cancer, renal cancer, colon cancer, gastric cancer, pancreatic cancer, ovarian cancer, melanoma, hepatoma, sarcoma, and lymphoma), exudative macular degeneration, proliferative diabetic retinopathy, ischemic retinopathy, retinopathy of prematurity, neovascular glaucoma, iritis rubeosis, corneal neovascularization, cyclitis, sickle cell retinopathy, and pterygium.

[0152] Compounds of the disclosure inhibit wild-type FGFR1, FGFR2, FGFR3, and / or FGFR4. In other aspects, compounds of the disclosure inhibit a mutated FGFR1, FGFR2, FGFR3, and / or FGFR4. In other aspects, compounds of the disclosure inhibit FGFR1, FGFR2, FGFR3, and / or FGFR4 that includes an FGFR kinase inhibitor mutation.

[0153] In some embodiments of any of the methods or uses described herein, the cancer (e.g., FGFR-associated cancer) is a hematological cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., FGFR-associated cancer) is a solid tumor.

[0154] In some embodiments of any of the methods or uses described herein, the cancer (e.g., FGFR-associated cancer) is a lung cancer (e.g., small cell lung carcinoma, non- small cell lung carcinoma, squamous cell carcinoma, lung adenocarcinoma, large cell carcinoma, mesothelioma, lung neuroendocrine carcinoma, smoking-associated lung cancer), prostate cancer, colorectal cancer (e.g., rectal adenocarcinoma), endometrial cancer (e.g., endometrioid endometrial cancer, endometrial adenocarcinoma), breast cancer (e.g., hormone-receptor-positive breast cancer, triple-negative breast cancer, neuroendocrine carcinoma of the breast), skin cancer (e.g., melanoma, cutaneous squamous cell carcinoma, basal cell carcinoma, large squamous cell carcinoma), gallbladder cancer, liposarcoma (e.g., dedifferentiated liposarcoma, myxoid liposarcoma), pheochromocytoma, myoepithelial carcinoma, urothelial carcinoma, spermatocytic seminoma, stomach cancer, head and neck cancer (e.g., head and neck (squamous) carcinoma, head and neck adenoid cystic adenocarcinoma), brain cancer (e.g., glialneural tumors, glioma, neuroblastoma, glioblastoma, pilocytic astrocytoma, Rosette forming glioneural tumor, dysembryoplastic neuroepithelial tumor, anaplastic astrocytoma, medulloblastoma, ganglioglioma, oligodendroglioma), malignant peripheral nerve sheath tumor, sarcoma (e.g., soft tissue sarcoma (e.g., leiomyosarcoma), osteosarcoma), esophageal cancer (e.g., esophageal adenocarcinoma), lymphoma, bladder cancer (e.g., bladder urothelial (transition cell) - 68 -4896-4398-0599.1120039.000146 | TYRA.037PCT carcinoma), cervical cancer (e.g., cervical squamous cell carcinoma, cervical adenocarcinoma), fallopian tube cancer (e.g., fallopian tube carcinoma), ovarian cancer (e.g., ovarian serous cancer, ovarian mucinous carcinoma), cholangiocarcinoma, adenoid cystic carcinoma, pancreatic cancer (e.g., pancreatic exocrine carcinoma, pancreatic ductal adenocarcinoma, pancreatic cancer intraepithelial neoplasia), salivary gland cancer (e.g., pleomorphic salivary gland adenocarcinoma, salivary adenoid cystic cancer), oral cancer (e.g., oral squamous cell carcinoma), uterine cancer, gastric or stomach cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumors, myeloma (e.g., multiple myeloma), lymphoepithelioma, anal cancer (e.g., anal squamous cell carcinoma), prostate cancer (e.g., prostate adenocarcinoma), renal cell carcinoma, thymic cancer, gastroesophageal junction adenocarcinoma, testicular cancer, rhabdomyosarcoma (e.g., alveolar rhabdomyosarcoma, embryonic rhabdomyosarcoma), renal papillary carcinoma, liver cancer (e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma), carcinoid, myeloid proliferative disorders (also called myeloid proliferative neoplasms (MPN); e.g., 8pll myeloproliferative syndrome (EMS, also called stem cell leukemia / lymphoma), acute myeloid leukemia (AML), chronic myeloid leukemia (CML)), lymphoma (e.g., T-cell lymphoma, T-lymphoblastic lymphoma, acute lymphoblastic leukemia (ALL), B-cell lymphoma), myeloid and lymphoid neoplasms, chronic neutrophilic leukemia, phosphaturic mesenchymal tumor, thyroid cancer (e.g. anaplastic thyroid carcinoma), or biliary duct cancer.

[0155] In other embodiments, the cancer is urothelial carcinoma, breast carcinoma, endometrial adenocarcinoma, ovarian carcinoma, primary glioma, cholangiocarcinoma, gastric adenocarcinoma, non-small cell lung carcinoma, pancreatic exocrine carcinoma, oral cancer, prostate cancer, bladder cancer, colorectal carcinoma, renal cell carcinoma, neuroendocrine carcinoma, myeloproliferative neoplasm, head and neck (squamous) cancer, melanoma, leiomyosarcoma, or sarcoma, or a combination thereof.

[0156] In other embodiments, the cancer is an FGFR-mutant cancer.

[0157] In further embodiments, the cancer is an FGFR3-mutant cancer.

[0158] In some embodiments of any of the methods or uses described herein, the cancer (e.g., FGFR-associated cancer) is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), cancer in adolescents, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, - 69 -4896-4398-0599.1120039.000146 | TYRA.037PCT Burkitt lymphoma, carcinoid tumor, unknown primary carcinoma, cardiac tumors, cervical cancer, childhood cancers, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, neoplasms by site, neoplasms, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, cutaneous angiosarcoma, bile duct cancer, ductal carcinoma in situ, embryonal tumors, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), germ cell tumor, gestational trophoblastic disease, glioma, hairy cell tumor, hairy cell leukemia, head and neck cancer, thoracic neoplasms, head and neck neoplasms, CNS tumor, primary CNS tumor, heart cancer, hepatocellular cancer, histiocytosis, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocytoma of bone, osteocarcinoma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer, midline tract carcinoma, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma, mycosis fungoides, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, neoplasms by site, neoplasms, myelogenous leukemia, myeloid leukemia, multiple myeloma, myeloproliferative neoplasms, nasal cavity and para nasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, lung neoplasm, pulmonary cancer, pulmonary neoplasms, respiratory tract neoplasms, bronchogenic carcinoma, bronchial neoplasms, oral cancer, oral cavity cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, para nasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary cancer, plasma cell neoplasm, pleuropulmonary blastoma, pregnancy-associated breast cancer, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, colon cancer, colonic neoplasms, renal cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sezary syndrome, skin cancer, Spitz tumors, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer, - 70 -4896-4398-0599.1120039.000146 | TYRA.037PCT stomach cancer, T-cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, unknown primary carcinoma, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms' tumor.

[0159] In some embodiments, a hematological cancer (e.g., hematological cancers that are FGFR associated cancers) is selected from the group consisting of leukemias, lymphomas (non-Hodgkin's lymphoma), Hodgkin's disease (also called Hodgkin's lymphoma), and myeloma, for instance, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large-cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T-cell ALL, AML with trilineage myelodysplasia (AML / TMDS), mixed lineage leukemia (MLL), myelodysplastic syndromes (MDSs), myeloproliferative disorders (MPD), and multiple myeloma (MM).

[0160] Additional examples of hematological cancers include myeloproliferative disorders (MPD) such as polycythemia vera (PV), essential thrombocytopenia (ET) and idiopathic primary myelofibrosis (IMF / IPF / PMF). In some embodiments, the hematological cancer (e.g., the hematological cancer that is a FGFR-associated cancer) is AML or CMML. In some embodiments, the cancer (e.g., the FGFR-associated cancer) is a solid tumor. Examples of solid tumors (e.g., solid tumors that are FGFR-associated cancers) include, for example, lung cancer (e.g., lung adenocarcinoma, non-small-cell lung carcinoma, squamous cell lung cancer), bladder cancer, colorectal cancer, brain cancer, testicular cancer, bile duct cancer cervical cancer, prostate cancer, and spermatolytic seminomas. See, for example, Turner and Grose, Nat. Rev. Cancer, 10(2):116-129, 2010.

[0161] In some embodiments, the cancer is selected from the group consisting of bladder cancer, brain cancer, breast cancer, cholangiocarcinoma, head and neck cancer, lung cancer, multiple myeloma, rhabdomyosarcoma, urethral cancer, and uterine cancer. In some embodiments, the cancer is selected from the group consisting of lung cancer, breast cancer, and brain cancer.

[0162] In some embodiments, a FGFRl-associated cancer is selected from the group consisting of lung cancer, breast cancer, and brain cancer. - 71 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0163] In some embodiments, the cancer is selected from the group consisting of breast cancer, uterine cancer, cholangiocarcinoma, and lung cancer.

[0164] In some embodiments, a FGFR2-associated cancer is selected from the group consisting of breast cancer, uterine cancer, cholangiocarcinoma, and lung cancer. In some embodiments, the cancer is selected from the group consisting of lung cancer, bladder cancer, urethral cancer, multiple myeloma, and head and neck cancer.

[0165] In some embodiments, a FGFR3-associated cancer is selected from the group consisting of lung cancer, bladder cancer, urethral cancer, multiple myeloma, and head and neck cancer.

[0166] In some embodiments, the cancer is selected from lung cancer, rhabdomyosarcoma, and breast cancer.

[0167] In some embodiments, a FGFR4-associated cancer is selected from lung cancer, rhabdomyosarcoma, and breast cancer.

[0168] In some aspects, the compounds of the disclosure are useful in treating cancers. In some embodiments, the cancer is associated with amplification or overexpression of FGFR1, for example, Breast cancer or carcinoma (e.g., hormone receptor-positive breast cancer, ductal carcinoma in situ (breast)), pancreatic ductal adenocarcinoma, pancreatic exocrine carcinoma, smoking-associated lung cancer, small cell lung cancer, lung adenocarcinoma, non-small cell lung cancer, squamous cell lung cancer or carcinoma, prostate cancer or carcinoma, ovarian cancer, fallopian tube carcinoma, bladder cancer, rhabdomyosarcoma, head and neck carcinoma (e.g., head and neck squamous cell carcinoma), esophageal cancer (e.g., esophageal squamous cell carcinoma), sarcoma (e.g., osteosarcoma), hepatocellular carcinoma, renal cell carcinoma, colorectal cancer (e.g., colorectal adenocarcinoma), prostate cancer, salivary gland tumors, glioblastoma multiforme, urinary bladder cancer, urothelial carcinoma, carcinoma of unknown primary, squamous non- lung tumors, gastric cancer, gastroesophageal junction carcinoma, adenoid cystic carcinoma, anal squamous cell carcinoma, oral squamous cell carcinoma, cholangiocarcinoma, hemangioendothelioma, leiomyosarcoma, melanoma, neuroendocrine carcinoma, squamous cell carcinoma, uterine carcinosarcoma.

[0169] In some aspects, the compounds of the disclosure are useful in treating cancers associated with amplification of FGFR2, for example, Gastric cancer, gastroesophageal junction adenocarcinoma, breast cancer (e.g., triple negative breast cancer), - 72 -4896-4398-0599.1120039.000146 | TYRA.037PCT colon cancer, colorectal cancer (e.g., colorectal adenocarcinoma), urothelial cancer, bladder adenocarcinoma, carcinoma of unknown primary, cholangiocarcinoma, endometrial adenocarcinoma, esophageal adenocarcinoma, gallbladder carcinoma, ovarian cancer, fallopian tube carcinoma, pancreatic exocrine carcinoma, sarcoma, squamous cell carcinoma.

[0170] In some aspects, the compounds of the disclosure are useful in treating cancers associated with overexpression of FGFR2, for example, Myxoid lipocarcinoma, rectal cancer, renal cell carcinoma, breast cancer.

[0171] In some aspects, the compounds of the disclosure are useful in treating cancers associated with upregulation of activity of FGFR3, for example, Colorectal cancer, hepatocellular carcinoma, pancreatic exocrine carcinoma. In some aspects, the compounds of the disclosure are useful in treating cancers associated with overexpression of activity of FGFR3, for example, Multiple myeloma, thyroid carcinoma. In some aspects, the compounds of the disclosure are useful in treating cancers associated with amplification of activity of FGFR3, for example, Bladder cancer and salivary adenoid cystic cancer, urothelial cancer, breast cancer, carcinoid, carcinoma of unknown primary, colorectal cancer (e.g., colorectal adenocarcinoma), gallbladder carcinoma, gastric cancer, gastroesophageal junction adenocarcinoma, glioma, mesothelioma, non-small cell lung carcinoma, small cell lung cancer, ovarian cancer, fallopian tube carcinoma, pancreatic exocrine carcinoma.

[0172] In some aspects, the compounds of the disclosure are useful in treating cancers associated with amplification of FGFR4, for example, Rhabdomyosarcoma, prostate cancer or carcinoma, breast cancer, urothelial cancer, carcinoid, carcinoma of unknown primary, esophageal adenocarcinoma, head and neck carcinoma, hepatocellular carcinoma, non-small cell lung carcinoma, ovarian cancer, fallopian tube carcinoma, peritoneal carcinoma, renal cell carcinoma.

[0173] In some aspects, the compounds of the disclosure are useful in treating cancers associated with upregulation of activity of FGFR4, for example, colorectal cancer, hepatocellular carcinoma, adrenal carcinoma, breast cancer.

[0174] In some aspects, the compounds of the disclosure are useful in treating cancers associated with overexpression of activity of FGFR4, for example, Pancreatic intraepithelial neoplasia, and pancreatic ductal adenocarcinoma.

[0175] In some aspects, the compounds of the disclosure are more selective for one FGFR than for another. As used herein, the "selectivity" of a compound for a first target over - 73 -4896-4398-0599.1120039.000146 | TYRA.037PCT a second target means that the compound has more potent activity at the first target than the second target. A fold selectivity can be calculated by any method known in the art. For example, a fold selectivity can be calculated by dividing the IC50 value (or Kd value) of a compound for the second target (e.g., FGFRl) by the IC50 value of the same compound for the first target (e.g., FGFR2 or FGFR3). An IC50 value can be determined by any method known in the art. In some embodiments, a compound is first determined to have an activity of less than 500 nM for the first target. In some embodiments, a compound is first determined to have an activity of less than 500 nM for the second target.

[0176] For example, in some aspects, the compounds of the disclosure are more selective for FGFR3 than for FGFR1. In some aspects, the compounds are at least 3-fold more selective for FGFR3 than for FGFR1. In some aspects, the compounds are 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 200, 500, or 1000 fold more selective for FGFR3 than for FGFR1.

[0177] In some aspects, the compounds of the disclosure are more selective for FGFR2 than for FGFR1. In some aspects, the compounds are at least 3-fold more selective for FGFR2 than for FGFR1. In some aspects, the compounds are 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 200, 500, or 1000 fold more selective for FGFR2 than for FGFR1.

[0178] In some aspects, the compounds of the disclosure are more selective for a first FGFR family member (e.g., FGFR2 or FGFR3) over a second FGFR family member (e.g., FGFR1 or FGFR4). In some aspects, the compounds of the disclosure are at least 3- fold more selective for a first FGFR family member over a second FGFR family member. In some aspects, the compounds are at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 200, 300, 400, 500, 600, 700, 800, 900, or at least 1000 fold more selective for a first FGFR family member over a second FGFR family member.

[0179] In some aspects, the compounds of the disclosure are more selective for an FGFR kinase over another kinase that is not an FGFR kinase. For example, the compounds of the disclosure are at least 3-fold more selective for an FGFR kinase over another kinase that is not an FGFR kinase. In some aspects, the compounds of the disclosure are at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 200, 300, 400, 500, 600, 700, 800, 900, or at least 1000 fold more selective for an FGFR kinase over another kinase that is not an FGFR kinase. Kinases that are not FGFR kinases include, for example, KDR kinase and Aurora B kinase. - 74 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0180] In some embodiments, the compounds of the disclosure exhibit brain and / or central nervous system (CNS) penetrance. Such compounds are capable of crossing the blood brain barrier and inhibiting a FGFR kinase in the brain and / or other CNS structures. In some embodiments, the compounds provided herein are capable of crossing the blood brain barrier in a therapeutically effective amount. For example, treatment of a subject with cancer (e.g., a FGFR-associated cancer such as a FGFR-associated brain or CNS cancer) can include administration (e.g., oral administration) of the compound to the subject. In some such embodiments, the compounds provided herein are useful for treating a primary brain tumor or metastatic brain tumor. For example, a FGFR-associated primary brain tumor or metastatic brain tumor.

[0181] In some embodiments, the compounds of the disclosure, exhibit one or more of high GI absorption, low clearance, and low potential for drug-drug interactions.

[0182] In some aspects, compounds of the disclosure can be used for treating a subject diagnosed with (or identified as having) a FGFR-associated disease or disorder (e.g., a FGFR-associated cancer) that include administering to the subject a therapeutically effective amount of a compound of the disclosure. Also provided herein are methods for treating a subject identified or diagnosed as having a FGFR-associated disease or disorder (e.g., a FGFR-associated cancer) that include administering to the subject a therapeutically effective amount of a compound of the disclosure. In some embodiments, the subject that has been identified or diagnosed as having a FGFR-associated disease or disorder (e.g., a FGFR- associated cancer) through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for identifying dysregulation of a FGFR gene, a FGFR kinase, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the FGFR- associated disease or disorder is a FGFR-associated cancer. For example, the FGFR- associated cancer can be a cancer that includes one or more FGFR inhibitor resistance mutations.

[0183] Also provided are methods for treating a disease or disorder in a subject in need thereof, the method comprising: (a) detecting a FGFR-associated disease or disorder in the subject; and (b) administering to the subject a therapeutically effective amount of a compound of the disclosure. Some embodiments of these methods further include - 75 -4896-4398-0599.1120039.000146 | TYRA.037PCT administering to the subject an additional therapy or therapeutic agent (e.g., a second FGFR inhibitor, a second compound of the disclosure, or an immunotherapy. In some embodiments, the subject was previously treated with a first FGFR inhibitor or previously treated with another treatment. In some embodiments, the subject is determined to have a FGFR- associated disease or disorder through the use of a regulatory agency-approved, e.g., FDA approved test or assay for identifying dysregulation of a FGFR gene, a FGFR kinase, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit.

[0184] Also provided are methods for treating cancer in a subject in need thereof, the method comprising: (a) detecting a FGFR-associated cancer in the subject ; and (b) administering to the subject a therapeutically effective amount of a compound of the disclosure. Some embodiments of these methods further include administering to the subject an additional therapy or therapeutic agent (e.g., a second FGFR inhibitor, a second compound of the disclosure, or an immunotherapy). In some embodiments, the subject was previously treated with a first FGFR inhibitor or previously treated with another anticancer treatment, e.g., at least partial resection of the tumor or radiation therapy. In some embodiments, the subject is determined to have a FGFR-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for identifying dysregulation of a FGFR gene, a FGFR kinase, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is a FGFR associated cancer. For example, the FGFR-associated cancer can be a cancer that includes one or more FGFR inhibitor resistance mutations. In some embodiments, the cancer is a FGFR associated cancer. For example, the FGFR- associated cancer can be a cancer that includes one or more FGFR activating mutations.

[0185] Also provided are methods of treating a subject that include performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of a FGFR gene, a FGFR kinase, or expression or activity or level of any of the same, and administering (e.g., specifically or selectively administering) a therapeutically effective amount of a compound of the disclosure or pharmaceutically acceptable salt or solvate thereof to the subject determined to have a dysregulation of a FGFR gene, a FGFR - 76 -4896-4398-0599.1120039.000146 | TYRA.037PCT kinase, or expression or activity or level of any of the same. Some embodiments of these methods further include administering to the subject an additional therapy or therapeutic agent (e.g., a second FGFR inhibitor, a second compound of the disclosure, or immunotherapy). In some embodiments of these methods, the subject was previously treated with a first FGFR inhibitor or previously treated with another anticancer treatment, e.g., at least partial resection of a tumor or radiation therapy. In some embodiments, the subject is a subject suspected of having a FGFR-associated disease or disorder (e.g., a FGFR-associated cancer), a subject presenting with one or more symptoms of a FGFR-associated disease or disorder (e.g., a FGFR-associated cancer), or a subject having an elevated risk of developing a FGFR-associated disease or disorder (e.g., a FGFR-associated cancer). In some embodiments, the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis. In some embodiments, the assay is a regulatory agency-approved assay, e.g., FDA-approved kit. In some embodiments, the assay is a liquid biopsy. Additional, non-limiting assays that may be used in these methods are described herein. Additional assays are also known in the art. In some embodiments, the dysregulation of a FGFR gene, a FGFR kinase, or expression or activity or level of any of the same includes one or more FGFR inhibitor resistance mutations.

[0186] Also provided herein are methods of selecting a treatment for a subject, wherein the methods include a step of performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of a FGFR gene, a FGFR kinase, or expression or activity or level of any of the same (e.g., one or more FGFR inhibitor resistance mutations), and identifying or diagnosing a subject determined to have a dysregulation of a FGFR gene, a FGFR kinase, or expression or activity or level of any of the same, as having a FGFR-associated cancer. Some embodiments further include administering the selected treatment to the subject identified or diagnosed as having a FGFR-associated cancer. For example, in some embodiments, the selected treatment can include administration of a therapeutically effective amount of a compound of the disclosure to the subject identified or diagnosed as having a FGFR-associated cancer. In some embodiments, the assay is an in vitro assay. For example, an assay that utilizes the next generation sequencing, immunohistochemistry, or break apart FISH analysis. In some embodiments, the assay is a regulatory agency-approved, e.g., FDA-approved, kit. In some embodiments, the assay is a liquid biopsy. - 77 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0187] Also provided herein are methods of treating a FGFR-associated cancer in a subject that include (a) administering one or more (e.g., two or more, three or more, four or more, five or more, or ten or more) doses of a first FGFR kinase inhibitor to a subject identified or diagnosed as having a FGFR associated cancer (e.g., any of the types of FGFR- associated cancers described herein) (e.g., identified or diagnosed as having a FGFR- associated cancer using any of the exemplary methods described herein or known in the art); (b) after step (a), determining a level of circulating tumor DNA in a biological sample (e.g., a biological sample comprising blood, serum, or plasma) obtained from the subject; (c) administering a therapeutically effective amount of a second FGFR inhibitor or a compound of the disclosure as a monotherapy or in conjunction with an additional therapy or therapeutic agent to a subject identified as having about the same or an elevated level of circulating tumor DNA as compared to a reference level of circulating tumor DNA (e.g., any of the reference levels of circulating tumor DNA described herein). In some examples of these methods, the reference level of circulating tumor DNA is a level of circulating tumor DNA in a biological sample obtained from the subject prior to step (a). Some embodiments of these methods further include determining the level of circulating tumor DNA in the biological sample obtained from the subject prior to step (a). In some examples of these methods, the reference level of circulating tumor DNA is a threshold level of circulating tumor DNA (e.g., an average level of circulating tumor DNA in a population of subjects having a similar FGFR-associated cancer and having a similar stage of the FGFR-associated cancer, but receiving a non-effective treatment or a placebo, or not yet receiving therapeutic treatment, or a level of circulating tumor DNA in a subject having a similar FGFR-associated cancer and having a similar stage of the FGFR-associated cancer, but receiving a non-effective treatment or a placebo, or not yet receiving therapeutic treatment). In some examples of these methods, the first FGFR inhibitor is: ARQ-087, ASP5878, AZD4547, B-701, BAY1179470, BAY1187982, BGJ398, brivanib, Debio 1347, dovitinib, E7090, erdafitinib, FPA144, HMPL-453, INCB054828, lenvatinib, lucitanib, LY3076226, MAX-40279, nintedanib, orantinib, pemigatinib, ponatinib, PRN1371, rogaratinib, sulfatinib, TAS-120 or RLY-4008.

[0188] Compounds of the disclosure can also be administered with additional therapy or therapeutic agents. In some aspects, the additional therapy or therapeutic agent includes one or more of radiation therapy, a chemotherapeutic agent (e.g., any of the exemplary chemotherapeutic agents described herein or known in the art), a checkpoint - 78 -4896-4398-0599.1120039.000146 | TYRA.037PCT inhibitor (e.g., any of the exemplary checkpoint inhibitors described herein or known in the art), surgery (e.g., at least partial resection of the tumor), and one or more other kinase inhibitors (e.g., any of the kinase inhibitors described herein or known in the art).

[0189] Compounds of the disclosure may also be useful as adjuvants to cancer treatment, that is, they can be used in combination with one or more additional therapies or therapeutic agents, for example a chemotherapeutic agent that works by the same or by a different mechanism of action. In some embodiments, a compound of the disclosure can be used prior to administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof can be administered one or more doses of a compound of the disclosure for a period of time and then under go at least partial resection of the tumor. In some embodiments, the treatment with one or more doses of a compound of the disclosure reduces the size of the tumor (e.g., the tumor burden) prior to the at least partial resection of the tumor. In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to standard therapy (e.g., administration of a chemotherapeutic agent, such as a first FGFR inhibitor or a multikinase inhibitor, immunotherapy, radiation, or a platinum-based agent (e.g., cisplatin)). In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to prior therapy (e.g., administration of a chemotherapeutic agent, such as a first FGFR inhibitor or a multikinase inhibitor, immunotherapy, radiation, or a platinum-based agent (e.g., cisplatin)).

[0190] In some embodiments of any the methods described herein, the compound of the disclosure is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapeutic) agents. Non-limiting examples of additional therapeutic agents include: other FGFR-targeted therapeutic agents (i.e. a first or second FGFR kinase inhibitor), other kinase inhibitors (e.g., receptor tyrosine kinase targeted therapeutic agents (e.g., Trk inhibitors or EGFR inhibitors)), signal transduction pathway inhibitors, checkpoint inhibitors, modulators of the apoptosis pathway (e.g. obataclax); cytotoxic chemotherapeutics, angiogenesis-targeted therapies, immune-targeted agents, including immunotherapy, and radiotherapy.

[0191] Also provided herein are methods of treating a disease or disorder, comprising administering to a subject in need thereof a pharmaceutical combination for - 79 -4896-4398-0599.1120039.000146 | TYRA.037PCT treating the disease or disorder which comprises (a) a compound of the disclosure, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use for the treatment of the disease or disorder, wherein the amounts of the compound of the disclosure and the additional therapeutic agent are together effective in treating the disease or disorder. In some embodiments, the compound of the disclosure, and the additional therapeutic agent are administered simultaneously as separate dosages. In some embodiments, the compound of the disclosure, and the additional therapeutic agent are administered as separate dosages sequentially in any order, in jointly therapeutically effective amounts, e.g. in daily or intermittently dosages. In some embodiments, the compound of the disclosure, and the additional therapeutic agent are administered simultaneously as a combined dosage. In some embodiments, the disease or disorder is a FGFR-associated disease or disorder. In some embodiments, the subject has been administered one or more doses of a compound of the disclosure, prior to administration of the pharmaceutical composition.

[0192] In some embodiments, the treatment period is at least 7 days (e.g., at least or about 8 days, at least or about 9 days, at least or about 10 days, at least or about 11 days, at least or about 12 days, at least or about 13 days, at least or about 14 days, at least or about 15 days, at least or about 16 days, at least or about 17 days, at least or about 18 days, at least or about 19 days, at least or about 20 days, at least or about 21 days, at least or about 22 days, at least or about 23 days, at least or about 24 days, at least or about 25 days, at least or about 26 days, at least or about 27 days, at least or about 28 days, at least or about 29 days, or at least or about 30 days).

[0193] In some embodiments, the treatment period is at least 21 days (e.g., at least or about 22 days, at least or about 23 days, at least or about 24 days, at least or about 25 days, at least or about 26 days, at least or about 27 days, at least or about 28 days, at least or about 29 days, at least or about 30 days, at least or about 31 days, at least or about 32 days, at least or about 33 days, at least or about 34 days, at least or about 35 days, at least or about 36 days, at least or about 37 days, at least or about 38 days, at least or about 39 days, or at least or about 40 days).

[0194] Also provided herein are pharmaceutical compositions that contain, as the active ingredient, a compound of the disclosure, in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the composition is - 80 -4896-4398-0599.1120039.000146 | TYRA.037PCT suitable for topical administration. In making the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to about 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. In some embodiments, the composition is formulated for oral administration. In some embodiments, the composition is formulated as a tablet or capsule.

[0195] The compositions comprising a compound of the disclosure can be formulated in a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units for human subjects and other subjects, each unit containing a predetermined quantity of active material (i.e., a compound of the disclosure) to produce the desired therapeutic effect, with a suitable pharmaceutical excipient.

[0196] In some embodiments, the compositions provided herein contain from about 5 mg to about 50 mg of the active ingredient, i.e., the compound of the disclosure. One having ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, or about 45 mg to about 50 mg of the active ingredient. In some embodiments, the compositions provided herein contain from about 50 mg to about 500 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 350 mg to about 400 mg, or about 450 mg to about 500 mg of the active ingredient. In some embodiments, the compositions provided herein contain from about 500 mg to about 1,000 mg of the active ingredient. One having ordinary skill in the art will appreciate that this embodies compounds or compositions containing about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to - 81 -4896-4398-0599.1120039.000146 | TYRA.037PCT about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of the active ingredient.

[0197] The active compound may be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual subject, the severity of the subject's symptoms, and the like.

[0198] In some embodiments, the compounds provided herein can be administered in an amount ranging from about 1 mg / kg to about 100 mg / kg. In some embodiments, the compound provided herein can be administered in an amount of about 1 mg / kg to about 20 mg / kg, about 5 mg / kg to about 50 mg / kg, about 10 mg / kg to about 40 mg / kg, about 15 mg / kg to about 45 mg / kg, about 20 mg / kg to about 60 mg / kg, or about 40 mg / kg to about 70 mg / kg. For example, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, or about 100 mg / kg. In some embodiments, such administration can be once-daily or twice-daily (BID) administration. Examples

[0199] The examples and preparations provided below further illustrate and exemplify the compounds of the disclosure and methods of preparing such compounds. It is to be understood that the scope of the disclosure is not limited in any way by the scope of the following examples and preparations.

[0200] In several embodiments, where single enantiomers are provided, the enantiomers may be separated by conventional means (chiral chromatography, preparing diastereomeric salts, chiral derivatization, crystallization, enzymatic reactions, etc.). In several embodiments, a chiral intermediate compound is purified to prepare an enantiomerically pure (or substantially enantiomerically pure, enantiomerically enriched, etc.) intermediate. - 82 -4896-4398-0599.1120039.000146 | TYRA.037PCT Example 1.5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2- [4-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperidine-4- carbonyl]piperazin-1-yl]pyridine-3-carbonitrile. Step 11Example 1 - 83 -4896-4398-0599.1120039.000146 | TYRA.037PCT Step 9Step 10

[0201] Step 1. (E)-N'-(2-Bromo-5-hydroxy-4-methoxybenzylidene)-4- methylbenzenesulfonohydrazide. p-Toluenesulfonyl hydrazide (0.56 g, 3.0 mmol, 1.0 equiv) was added to a solution of 2-bromo-5-hydroxy-4-methoxy-benzaldehyde (0.7 g, 3.0 mmol, 1.0 equiv) in methanol (7.0 mL) at rt. The resulting mixture was heated at 60 °C for 2 h. The reaction was cooled to rt and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (20 mL), then heptanes (80 mL) was added to give a light- yellow solid (1.21 g, 100%). LCMS m / z = 399.0 (M+H).

[0202] Step 2.6-Methoxy-1-tosyl-1H-indazol-5-ol. Copper(I) oxide (0.22 g, 1.5 mmol, 0.5 equiv) was added to a solution of (E)-N'-(2-Bromo-5-hydroxy-4- methoxybenzylidene)-4-methylbenzenesulfonohydrazide (1.2 g, 3.0 mmol, 1.0 equiv) in isoamyl alcohol (30 mL) at room temperature. After heating at 132 °C for 2 hours, the mixture was cooled to room temperature and diluted with water (80 mL). The mixture was extract with ethyl acetate (4 x 50 mL). The combined organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated onto silica gel (8.0 g) and purified on a Biotage automated purification system (Biotage Sfar Silica, 50 g; 0% to 100% ethyl acetate in heptanes) to give a light yellow solid (0.66 g, 70% yield). LCMS m / z = 319.1 (M+H).

[0203] Step 3. (R)-5-(1-(3,5-Dichloropyridin-4-yl)ethoxy)-6-methoxy-1-tosyl-1H- indazole. (1S)-1-(3,5-dichloro-4-pyridyl)ethyl] methanesulfonate (0.57 g, 2.1 mmol, 1.0 equiv) and cesium carbonate (1.03 g, 3.2 mmol, 1.5 equiv) were added to a solution of 6- methoxy-1-tosyl-1H-indazol-5-ol (0.67 g, 2.1 mmol, 1.0 equiv) in acetonitrile (21 mL) at room temperature. After heating at 90 °C overnight, the mixture was cooled to room temperature and concentrated onto silica gel (6.0 g) under reduced pressure. The product was - 84 - 4896-4398-0599.1120039.000146 | TYRA.037PCT purified on a Biotage automated purification system (Sorbtech silica, 40 g), eluting with a gradient of 0% to 60% ethyl acetate in heptanes to give a white solid (0.71 g, 70% yield). LCMS m / z= 492.1 (M+H).

[0204] Step 4. (R)-5-(1-(3,5-Dichloropyridin-4-yl)ethoxy)-6-methoxy-1H- indazole.1M Tetrabutylammonium fluoride in THF (7.2 mL, 7.2 mmol, 18.0 equiv) was added to a solution of (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy-1-tosyl-1H- indazole (0.20 g, 0.4 mmol, 1.0 equiv) in tetrahydrofuran (4 mL) at room temperature. After heating at 50 °C for 4 days, the solvent was removed under reduced pressure. The residue was concentrated onto silica gel (2.0 g) and purified on a Biotage automated purification system (Sorbtech silica, 12 g), eluting with a gradient of 0% to 100% ethyl acetate in heptanes to give a white solid (74.7 mg, 54%). LCMS m / z = 338.0 (M+H).

[0205] Step 5. (R)-5-(1-(3,5-Dichloropyridin-4-yl)ethoxy)-3-iodo-6-methoxy-1H- indazole. Potassium hydroxide (27.9 mg, 0.50 mmol, 2.25 equiv) and iodine (84.1 mg, 0.33 mmol, 1.5 equiv) were added to a solution of (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-6- methoxy-1H-indazole (74.7 mg, 0.22 mmol, 1.0 equiv) in N,N-dimethylformamide (2.2 mL) at 0 °C. The resulting mixture was allowed to warm up to room temperature and stirred overnight. The reaction was diluted with ethyl acetate (10 mL) and washed with water (4 x 5 mL). The organic layer was dried over sodium sulfate and concentrated onto silica gel (1.5 g) under reduced pressure. The product was purified on a Biotage automated purification system (Sorbtech silica, 12 g), eluting with a gradient of 0% to 100% ethyl acetate in heptanes to give an off-white solid (80 mg, 77%). LCMS m / z = 463.9 (M+H).

[0206] Step 6.5-((R)-1-(3,5-Dichloropyridin-4-yl)ethoxy)-3-iodo-6-methoxy-1- (tetrahydro-2H-pyran-2-yl)-1H-indazole.5-[(1R)-1-(3,5-Dichloro-4-pyridyl)ethoxy]-3-iodo- 6-methoxy-1H-indazole (0.5 g, 1.1 mmol, 1 equiv) was treated with 3,4-dihydro-2H-pyran (0.2 mL, 2.2 mmol, 2 equiv) and p-toluenesulfonic acid monohydrate (10 mg, 0.05 mmol, 0.05 equiv) in anhydrous dichloromethane (6 mL) at room temperature overnight. The mixture was diluted with dichloromethane (8 mL) and washed with water (8 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure onto silica gel (6 g). The residue was purified on a Biotage automated chromatography system (Sorbtech, 12 g silica gel column), eluting with a gradient of 0 to 20% ethyl acetate in heptanes to give a white solid (510 mg, 86%). LCMS m / z = 548 (M+H). - 85 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0207] Step 7.2-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3- carbonitrile. To a solution of 5-bromo-2-fluoro-pyridine-3-carbonitrile (10 g, 49.8 mmol, 1.0 eq) and bis(pinacolato)diboron (25.3 g, 99.5 mmol, 2.0 eq) in dioxane (200 mL) was added KOAc (20.6 g, 149.3 mmol, 3.0 eq) and Pd(dppf)Cl2 (2.0 g, 20wt%). The reaction mixture was stirred for 5 h at 90 ºC under N2 protection. After the reaction was completed, the solid was filtered out and the filtrate was concentrated in vacuum. The crude product was purified by silica gel column (Petroleum Ether / EtOAc = 10 / 1) to give a white solid (12 g, 59%). LCMS m / z = 249.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 1.6 Hz, 1H), 8.63 (dd, J = 9.2 Hz, 1.6 Hz, 1H), 1.32 (s, 12H).

[0208] Step 8.5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1- tetrahydropyran-2-yl-indazol-3-yl]-2-fluoro-pyridine-3-carbonitrile. To a solution of 2- fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carbonitrile (1.0 g, 4.0 mmol, 2.2 eq) and 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-iodo-6-methoxy-1- tetrahydropyran-2-yl-indazole (1.0 g, 1.8 mmol, 1.0 eq) in dioxane (20 mL) and H2O (2 mL) was added K2CO3 (745 mg, 5.4 mmol, 3.0 eq) and Pd(dppf)Cl2 (100 mg, 10%wt) at rt. The mixture was stirred for 2 h at 90 °C under N2 protection. After the reaction was completed, the solid was filtered out and the filtrate was concentrated in vacuum. The crude product was purified by silica gel column (Petroleum Ether / EtOAc = 1 / 1) to give an off-white solid (900 mg, 91% yield). LCMS m / z = 542.2 (M+H).

[0209] Step 9. tert-Butyl 4-(4-(3-cyano-5-(5-((R)-1-(3,5-dichloropyridin-4- yl)ethoxy)-6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyridin-2- yl)piperazine-1-carbonyl)piperidine-1-carboxylate. A suspension of 5-[5-[(1R)-1-(3,5- dichloro-4-pyridyl)ethoxy]-6-methoxy-1-tetrahydropyran-2-yl-indazol-3-yl]-2-fluoro- pyridine-3-carbonitrile (252 mg, 0.46 mmol, 1 equiv) in acetonitrile (10 mL) was sequentially treated with N,N-diisopropylethylamine (0.30 mL, 1.7 mmol, 3.7 equiv) and tert-butyl 4- (piperazine-1-carbonyl)piperidine-1-carboxylate (170 mg, 0.57 mmol, 1.2 equiv). After stirring at room temperature overnight, the mixture was heated at 60 °C for 48 hours. The reaction was cooled to room temperature, diluted with water (20 mL) and saturated brine (5 mL), then extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with saturated brine (10 mL), filtered, and concentrated under reduced pressure onto silica gel. The residue was purified on a Biotage automated chromatography system - 86 -4896-4398-0599.1120039.000146 | TYRA.037PCT (Sorbtech 40 g silica gel column), eluting with a gradient of 10 to 100% ethyl acetate in hexanes to give an off-white solid (328 mg, 86%). LCMS m / z = 819 (M+H).

[0210] Step 10. (R)-5-(5-(1-(3,5-Dichloropyridin-4-yl)ethoxy)-6-methoxy-1H- indazol-3-yl)-2-(4-(piperidine-4-carbonyl)piperazin-1-yl)nicotinonitrile bis(trifluoroacetic acid) salt. tert-Butyl 4-(4-(3-cyano-5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-6-methoxy- 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyridin-2-yl)piperazine-1-carbonyl)piperidine- 1-carboxylate (320 mg, 0.39 mmol, 1 equiv) in dichloromethane (2.5 mL) was treated with trifluoroacetic acid (2.5 mL) at room temperature overnight. The reaction was concentrated under reduced pressure then reconcentrated from dichloromethane (2 x 10 mL) and from acetonitrile (20 mL) to give an amber oil (330 mg, 100%). This material was used directly in the next step.

[0211] Step 11.5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H- indazol-3-yl]-2-[4-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperidine-4- carbonyl]piperazin-1-yl]pyridine-3-carbonitrile. (R)-5-(5-(1-(3,5-Dichloropyridin-4- yl)ethoxy)-6-methoxy-1H-indazol-3-yl)-2-(4-(piperidine-4-carbonyl)piperazin-1- yl)nicotinonitrile bis(trifluoroacetic acid) salt from step 2 (165 mg, 0.19 mmol) in dimethyl sulfoxide (3 mL) was treated with N,N-diisopropylethylamine (1 mL, 5.7 mmol, 30 equiv) and 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (59 mg, 0.21 mmol, 1.1 equiv) at 80 °C for 24 hours. The reaction was cooled to room temperature then directly purified on a Biotage automated chromatography system (RediSep Gold C18100 g column), eluting with a gradient of 0 to 100% acetonitrile in water to give a yellow solid (50 mg, 29% yield over two steps). LCMS m / z = 891 (M+H); 1H NMR (400 MHz, DMSO-d6) δ = 13.05 (s, 1H), 11.06 (s, 1H), 8.81 (d, J = 2.3 Hz, 1H), 8.59 (s, 2H), 8.24 (d, J = 2.3 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.26 (dd, J = 2.2, 8.7 Hz, 1H), 7.09 (s, 1H), 7.02 (s, 1H), 6.00 (q, J = 6.7 Hz, 1H), 5.07 (dd, J = 5.4, 12.8 Hz, 1H), 4.09 (br d, J = 13.0 Hz, 2H), 3.86 (s, 3H), 3.80 (br s, 4H), 3.69 (br d, J = 10.1 Hz, 4H), 3.15-3.01 (m, 3H), 2.89 (ddd, J = 5.4, 13.8, 17.2 Hz, 1H), 2.64-2.51 (m, 2H), 2.06-1.98 (m, 1H), 1.81-1.73 (m, 5H), 1.71-1.60 (m, 2H). Example 2.5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2- [4-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]piperidine-4- carbonyl]piperazin-1-yl]pyridine-3-carbonitrile. - 87 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0212] 5-(5-((R)-1-(3,5-Dichloropyridin-4-yl)ethoxy)-6-methoxy-1H-indazol-3- yl)-2-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidine-4- carbonyl)piperazin-1-yl)nicotinonitrile. (R)-5-(5-(1-(3,5-Dichloropyridin-4-yl)ethoxy)-6- methoxy-1H-indazol-3-yl)-2-(4-(piperidine-4-carbonyl)piperazin-1-yl)nicotinonitrile bis(trifluoroacetic acid) salt (165 mg, 0.19 mmol) in dimethyl sulfoxide (3 mL) was treated with N,N-diisopropylethylamine (1 mL, 5.7 mmol, 30 equiv) and 2-(2,6-dioxo-3-piperidyl)- 4-fluoro-isoindoline-1,3-dione (59 mg, 0.21 mmol, 1.1 equiv) at 80 °C for 24 hours. The reaction was cooled to room temperature then directly purified on a Biotage automated chromatography system (RediSep Gold C18100 g column), eluting with a gradient of 0 to 100% acetonitrile in water to give a yellow solid (61 mg, 36%). LCMS m / z = 891 (M+H); 1H NMR (400 MHz, DMSO-d6) δ = 13.05 (s, 1H), 11.08 (s, 1H), 8.81 (d, J = 2.3 Hz, 1H), 8.59 (s, 2H), 8.24 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 7.3, 8.4 Hz, 1H), 7.38-7.30 (m, 2H), 7.08 (s, 1H), 7.02 (s, 1H), 6.00 (q, J = 6.7 Hz, 1H), 5.10 (dd, J = 5.4, 12.8 Hz, 1H), 3.86 (s, 3H), 3.83- 3.66 (m, 10H), 3.05-2.83 (m, 4H), 2.63-2.52 (m, 2H), 2.03 (br d, J = 5.3 Hz, 1H), 1.88-1.74 (m, 7H). Example 3.4-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-1-piperidyl]-2-(2,6-dioxo-3- piperidyl)isoindoline-1,3-dione. - 88 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0213] Step 1.5-((R)-1-(3,5-Dichloropyridin-4-yl)ethoxy)-3-iodo-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazole. A mixture of 3-iodo-1-tetrahydropyran-2-yl-indazol-5-ol (1.0 g, 2.90 mmol, 1.0 equiv), [(1S)-1-(3,5-dichloro-4-pyridyl)ethyl] methanesulfonate (780 mg, 2.90 mmol, 1.0 equiv) and cesium carbonate (1.41 g, 14.45 mmol, 1.5 equiv) in N,N- dimethylformamide (20 mL) was heated at 130 °C for 16 h. The volatiles were removed under reduced pressure and the residue was suspended in saturated ammonium chloride (50 mL). The solution was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified on a Büchi automated chromatography system (Sorbtech 40 g silica gel column), eluting with a gradient of 0 to 30% ethyl acetate in heptanes to give a white solid (1.01 g, 88%). LCMS m / z = 517.2 (M+H).

[0214] Step 2. (R)-5-(1-(3,5-Dichloropyridin-4-yl)ethoxy)-3-iodo-1H-indazole. A mixture of 5-((R)-1-(3,5-Dichloropyridin-4-yl)ethoxy)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazole. A mixture of 3-iodo-1-tetrahydropyran-2-yl-indazol-5-ol (1.0 g, 1.93 mmol, 1 equiv) in dichloromethane (10 mL) was treated with trifluoroacetic acid (3 mL, 39.2 mmol, 20 equiv) at room temperature for 24 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (100 mL), washed with saturated - 89 -4896-4398-0599.1120039.000146 | TYRA.037PCT sodium bicarbonate (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was dried at room temperature under vacuum overnight to give an orange solid (1.05 g, >100%) that was used directly in the next step. LCMS m / z = 434 (M+H); 1H NMR (400 MHz, DMSO-d6) δ = 13.37 (br s, 1H), 8.60 (s, 2H), 7.46 (d, J = 8.9 Hz, 1H), 7.13 (dd, J = 2.4, 9.0 Hz, 1H), 6.59 (d, J = 2.3 Hz, 1H), 6.07 (q, J = 6.6 Hz, 1H), 1.75 (d, J = 6.6 Hz, 3H).

[0215] Step 3. (R)-5-(1-(3,5-Dichloropyridin-4-yl)ethoxy)-3-(6-fluoropyridin-3- yl)-1H-indazole. A solution of (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-iodo-1H- indazole (1.0 g, 2.3 mmol, 1 equiv) and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (0.67 g, 2.995 mmol,1.3 equiv) in 20 to 1 mixture of 1,4-dioxane and DI water (21 mL) was sparged with nitrogen for 15 minutes. Potassium carbonate (0.825 g, 5.98 mmol, 2.6 equiv) and (1,1'-bis(diphenylphosphino) ferrocene)palladium(II) dichloride (168 mg, 0.23 mmol, 0.01 equiv) were added and the reaction mixture was sparged with nitrogen for an additional 5 minutes. The reaction was heated at 90 °C for 2 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure and diluted with saturated brine (30 mL) and dichloromethane (30 mL). The layers were separated, and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was absorbed onto silica gel (2 g) and purified on an Interchim automated chromatography system (Sorbtech 40 g silica gel cartridge), eluting with a gradient of 20 to 80% ethyl acetate in heptanes to give a yellow solid (0.42 g, 45%). LCMS m / z = 403.1 (M+H); 1H NMR (400 MHz, CDCl3) δ = 10.55 (br s, 1H), 8.68 (d, J = 2.1 Hz, 1H), 8.43 (s, 2H), 8.24 (dt, J = 2.4, 8.1 Hz, 1H), 7.39 (dd, J = 0.8, 8.7 Hz, 1H), 7.20-7.14 (m, 2H), 7.06 (dd, J = 2.8, 8.4 Hz, 1H), 6.06 (q, J = 6.7 Hz, 1H), 1.82 (d, J = 6.6 Hz, 3H).

[0216] Step 4. tert-Butyl (R)-6-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H- indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate. A mixture of (R)-5-(1- (3,5-dichloropyridin-4-yl)ethoxy)-3-(6-fluoropyridin-3-yl)-1H-indazole (0.295 g, 0.732 mmol, 1 equiv), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (0.29 g, 1.464 mmol, 2 equiv), and potassium carbonate (0.4 g,2.93 mmol, 4 equiv) in anhydrous N- methylpyrrolidone was heated at 120 ºC for 16 hours. The reaction mixture was filtered through a syringe filter and the filtrate was pre-absorbed on Celite (5 g). The material was purified on an Interchim automated chromatography system (RediSep Rf Gold HP C18, 15.5 g cartridge), eluting with a gradient of 0 to 100% acetonitrile in water. The fractions - 90 -4896-4398-0599.1120039.000146 | TYRA.037PCT containing product were collected and lyophilized to give a yellowish solid (0.3 g, 71%). LCMS m / z = 581 (M+H).

[0217] Step 5. (R)-3-(6-(2,6-Diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-5-(1-(3,5- dichloropyridin-4-yl)ethoxy)-1H-indazole. A solution of tert-butyl (R)-6-(5-(5-(1-(3,5- dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2- carboxylate (50 mg, 0.086 mmol, 1 equiv) in anhydrous dichloromethane (2 mL) was treated with trifluoroacetic acid (0.53 mL, 6.88 mmol, 80 equiv) at room temperature for 16 hours. Additional trifluoroacetic acid (0.23 mL, 3.01 mmol, 35 equiv) was added and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to dryness. The residue was dissolved in methanol (10 mL), treated with MP-carbonate resin (3.2 mmol / g, 1 g), stirred for 30 minutes, filtered, and concentrated under reduced pressure. The residue was absorbed onto Celite (1 g) and purified on an Interchim automated chromatography system (RediSep Rf Gold HP C18, 15.5 g cartridge), eluting with a gradient of 0 to 100% acetonitrile in water. The fractions containing product were collected and lyophilized to give a white solid (30 mg, 73%). LCMS m / z = 481.1 (M+H); 1H NMR (400 MHz, DMSO-d6) δ = 13.00 (br s, 1H), 8.59 (s, 2H), 8.50 (d, J = 1.8 Hz, 1H), 7.84 (dd, J = 2.3, 8.7 Hz, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.16 (d, J = 2.1 Hz, 1H), 7.08 (dd, J = 2.3, 9.0 Hz, 1H), 6.51 (d, J = 8.4 Hz, 1H), 6.10 (q, J = 6.6 Hz, 1H), 4.20-3.82 (m, 5H), 3.66 (br s, 4H), 1.76 (d, J = 6.6 Hz, 3H).

[0218] Step 6. tert-Butyl 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)piperidine-4-carboxylate. A mixture of 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3- dione (0.5 g, 1.81 mmol, 1.0 equiv), tert-butyl piperidine-4-carboxylate (0.5 g, 2.72 mmol, 1.5 equiv) and N,N-diisopropylethylamine (3.15 mL, 18.1 mmol, 10 equiv) in DMSO (5.0 mL) was stirred at 80 °C for 16 hours. After cooling to room temperature, the mixture was poured into water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated brine (2 x 15 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dried under vacuum for 5 hours to give a yellow solid (0.8 g, 90%), that was used directly in the next step. LCMS m / z = 442.2 (M+H).

[0219] Step 7.1-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidine- 4-carboxylic acid hydrochloride.4M HCl in 1,4-dioxane (3.0 mL, 12 mmol, 30 equiv) was added to a suspension of tert-Butyl 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)piperidine-4-carboxylate (200 mg, 1 equiv, 0.4 mmol) in 1,4-dioxane (1.0 mL) and the - 91 -4896-4398-0599.1120039.000146 | TYRA.037PCT resulting mixture was stirred at 50 °C for 16 hours. After cooling to room temperature, the volatiles were evaporated under reduced pressure and the residue was dried under vacuum at 40 °C for 1 hour to give a yellow solid as the HCl salt(190 mg) that was used directly in the next step. LCMS m / z = 386.1 (M+H, free base).

[0220] Step 8.4-(4-(6-(5-(5-((R)-1-(3,5-Dichloropyridin-4-yl)ethoxy)-1H-indazol- 3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)piperidin-1-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione. N,N-diisopropylethylamine (180 µL, 1.02 mmol, 5.0 equiv) was added to a suspension of 1-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin- 4-yl)piperidine-4-carboxylic acid hydrochloride (86 mg, 0.20 mmol, 1.0 equiv), hexafluorophosphate azabenzotriazole tetramethyluronium (93 mg, 0.25 mmol, 1.2 equiv) and compound (R)-3-(6-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-5-(1-(3,5- dichloropyridin-4-yl)ethoxy)-1H-indazole (116 mg, 0.20 mmol, 1.0 equiv) in N,N- dimethylacetamide (2.0 mL) at room temperature. The reaction was stirred at room temperature for 64 hours. The mixture was purified directly on a Biotage automated chromatography system (RediSep Gold C1830 g column), eluting with a gradient of 0 to 70% acetonitrile in water to give a yellow solid (37 mg, 21%). LCMS m / z = 848.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ = 12.99 (s, 1H), 11.08 (s, 1H), 8.59 (s, 2H), 8.52 (d, J = 2.1 Hz, 1H), 7.87 (dd, J = 2.3, 8.6 Hz, 1H), 7.69 (dd, J = 7.2, 8.4 Hz, 1H), 7.46 (d, J = 9.0 Hz, 1H), 7.34 (t, J = 7.8 Hz, 2H), 7.17 (s, 1H), 7.09 (dd, J = 2.2, 9.0 Hz, 1H), 6.55 (d, J = 8.6 Hz, 1H), 6.11 (q, J = 6.7 Hz, 1H), 5.10 (dd, J = 5.4, 12.8 Hz, 1H), 4.45 (s, 2H), 4.18 (s, 4H), 4.10 (s, 2H), 3.72 (br d, J = 9.8 Hz, 2H), 3.00-2.83 (m, 3H), 2.63-2.52 (m, 2H), 2.47-2.41 (m, 1H), 2.07-1.99 (m, 1H), 1.76 (br d, J = 6.6 Hz, 7H). Example 4.5-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-3- fluoro-2-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-1-piperidyl]-2-(2,6-dioxo-3- piperidyl)isoindoline-1,3-dione Step 3 Step 4Example 4 - 92 -4896-4398-0599.1120039.000146 | TYRA.037PCTStep 1Step 2

[0221] Step 1.5-[(1R)-1-(3,5-Dichloro-4-pyridyl)ethoxy]-3-(5,6-difluoro-3- pyridyl)-1-tetrahydropyran-2-yl-indazole. To a solution of 5-[(1R)-1-(3,5-dichloro-4- pyridyl)ethoxy]-3-iodo-1-tetrahydropyran-2-yl-indazole (4.50 g, 8.68 mmol, 1.0 eq) and 2,3- difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.14 g, 13.03 mmol, 1.5 eq) in dioxane (50 mL) and water (5 mL) was added K2CO3(3.60 g, 26.05 mmol, 3.0 eq) and Pd(dppf)Cl2(708 mg, 0.87 mmol, 0.1 eq). The reaction mixture was stirred for 3 h at 90 °C under N2 protection. After the reaction was completed, the solid was filtered out and the filtrate was concentrated in vacuum. The crude product was purified by silica gel column (Petroleum Ether / EtOAc = 10 / 1) to give a white solid (2.3 g, 52%). LCMS m / z = 505.2 (M+H).

[0222] Step 2. tert-Butyl 6-(5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1- (tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-3-fluoropyridin-2-yl)-2,6- diazaspiro[3.3]heptane-2-carboxylate. tert-Butyl 2-(5-(5-((R)-1-(3,5-dichloropyridin-4- yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-3-fluoropyridin-2-yl)-2,5- diazaspiro[3.4]octane-5-carbo (400 mg, 0.792 mmol, 1 equiv) was treated with tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemi-oxylate (231 mg, 0.475 mmol, 0.6 equiv) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.6 mL, 3.96 mmol, 5 equiv) in 1-methoxy-2- propanol (10.0 mL). After heating at 100 °C for 24 hours, the reaction was cooled to room temperature and diluted with water (25 mL). The resulting white precipitate was filtered and dried under vacuum at 40 °C overnight to give a white solid (459 mg, 85%). LCMS m / z = 682.1 (M+H).

[0223] Step 3. (R)-5-(1-(3,5-Dichloropyridin-4-yl)ethoxy)-3-(5-fluoro-6-(2,6- diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1H-indazole. tert-Butyl 6-(5-(5-((R)-1-(3,5- dichloropyridin-4-yl)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-3- - 93 - 4896-4398-0599.1120039.000146 | TYRA.037PCT fluoropyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (459 mg, 0.766 mmol, 1 equiv) was dissolved in a mixture of dichloromethane (5 mL) and trifluoroacetic acid (5 mL) then stirred at room temperature for 6 hours. Saturated sodium carbonate was adjusting the pH >8, forming an off-white precipitate that was insoluble in dichloromethane and water. The precipitate was filtered to give an off-white solid, which was dried under vacuum at 40 °C overnight. The crude product was purified on a Biotage automated chromatography system (RediSep C18120 g column) eluting with a gradient of 0 to 100% acetonitrile in water to give a white solid (90 mg, 24%). LCMS m / z = 499.1 (M+H); 1H NMR (400 MHz, DMSO-d6) δ = 13.10 (br s, 1H), 8.57 (s, 2H), 8.38-8.35 (m, 1H), 7.69 (dd, J = 1.6, 13.2 Hz, 1H), 7.47 (d, J = 9.0 Hz, 1H), 7.19 (d, J = 2.1 Hz, 1H), 7.10 (dd, J = 2.2, 9.0 Hz, 1H), 6.13 (q, J = 6.6 Hz, 1H), 4.22 (br s, 4H), 4.01 (br s, 1H), 3.78-3.57 (m, 4H), 1.76 (d, J = 6.6 Hz, 3H).

[0224] Step 4.5-(4-(6-(5-(5-((R)-1-(3,5-Dichloropyridin-4-yl)ethoxy)-1H-indazol- 3-yl)-3-fluoropyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)piperidin-1-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione. N,N-Diisopropylethylamine (180 µL, 1.02 mmol, 5.0 equiv) was added to a suspension of 3-[6-(2,6-diazaspiro[3.3]heptan-2-yl)-5-fluoro-3- pyridyl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole (102 mg, 0.20 mmol, 1.0 equiv), hexafluorophosphate azabenzotriazole tetramethyluronium (93 mg, 0.25 mmol, 1.2 equiv) and 1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperidine-4-carboxylic acid HCl salt (95 mg, 0.20 mmol, 1.0 equiv) in N,N-dimethylacetamide (2.0 mL) at room temperature. The reaction was stirred at room temperature for 18 hours. The mixture was purified directly on a Biotage automated chromatography system (RediSep Gold C1830 g column), eluting with a gradient of 0 to 50% acetonitrile in water to give a yellow solid (33 mg, 19%). LCMS m / z = 866.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ = 13.12 (s, 1H), 11.06 (s, 1H), 8.57 (s, 2H), 8.38 (s, 1H), 7.72 (dd, J = 1.7, 13.1 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.48 (d, J = 9.0 Hz, 1H), 7.33 (d, J = 1.8 Hz, 1H), 7.25 (dd, J = 2.1, 8.7 Hz, 1H), 7.20 (s, 1H), 7.10 (dd, J = 2.2, 9.0 Hz, 1H), 6.14 (q, J = 6.7 Hz, 1H), 5.07 (dd, J = 5.4, 12.8 Hz, 1H), 4.44 (s, 2H), 4.36-4.26 (m, 4H), 4.16-4.00 (m, 4H), 3.12-3.01 (m, 2H), 2.95-2.82 (m, 1H), 2.63-2.52 (m, 3H), 2.07-1.97 (m, 1H), 1.81-1.68 (m, 5H), 1.63-1.51 (m, 2H). Example 5. 5-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-1-piperidyl]-2-(2,6-dioxo-3- piperidyl)isoindoline-1,3-dione. - 94 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0225] Step 1. tert-Butyl 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)piperidine-4-carboxylate. A mixture of 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3- dione (0.5 g, 1.8 mmol, 1 equiv), tert-butyl piperidine-4-carboxylate (0.5 g, 2.7 mmol, 1.5 equiv), and N,N-diisopropylethylamine (3.15 mL, 18.1 mmol, 10 equiv) in DMSO (5.0 mL) was stirred at 80 °C for 16 hours. After cooling to room temperature, the mixture was poured into water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated brine (2 x 15 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (Biotage Sfar HC 10 g column), eluting with a gradient of 0 to 50% ethyl acetate in hexanes to give a yellow solid (686 mg, 77%). LCMS m / z = 442.2 (M+H).

[0226] Step 2.1-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine- 4-carboxylic acid hydrochloride.4M HCl in 1,4-dioxane (1.5 mL, 6.0 mmol, 30 equiv) was added to a suspension of tert-butyl 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)piperidine-4-carboxylate (100 mg, 0.2 mmol, 1 equiv) in 1,4-dioxane (0.5 mL),and the mixture was stirred at 50 °C for 19 hours. After cooling to room temperature, the volatiles were evaporated under reduced pressure and the residue was dried under vacuum at 40 °C for 2 hours to give an off-white solid (120 mg). This material was used directly in the next step. LCMS m / z = 386.2 (M+H, free base).

[0227] Step 3.5-(4-(6-(5-(5-((R)-1-(3,5-Dichloropyridin-4-yl)ethoxy)-1H-indazol- 3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)piperidin-1-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione. N,N-Diisopropylethylamine (180 µL, 1.02 mmol 5.0 equiv) was added to a suspension of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin- 5-yl)piperidine-4-carboxylic acid hydrochloride (100 mg, 0.20 mmol, 1.0 equiv), hexafluorophosphate azabenzotriazole tetramethyluronium (93 mg, 0.25 mmol, 1.2 equiv) and 3-[6-(2,6-diazaspiro[3.3]heptan-2-yl)-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-4- - 95 -4896-4398-0599.1120039.000146 | TYRA.037PCT pyridyl)ethoxy]-1H-indazole (116 mg, 0.20 mmol, 1.0 equiv) in N,N-dimethylacetamide (2.0 mL) at room temperature. The reaction was stirred at room temperature for 16 hours. The mixture was purified directly on a Biotage automated chromatography system (RediSep Gold C1830 g column), eluting with a gradient of 0 to 50% acetonitrile in water to give a yellow solid (120 mg). The product was further purified on a Biotage automated chromatography system (RediSep Gold C1830 g column), eluting with a gradient of 0 to 45% acetonitrile in water to give a yellow solid (47 mg, 27% yield over two steps). LCMS m / z = 848.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ = 13.00 (br s, 1H), 11.06 (br s, 1H), 8.59 (s, 2H), 8.52 (d, J = 1.7 Hz, 1H), 7.87 (dd, J = 2.1, 8.5 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.33 (s, 1H), 7.25 (br d, J = 8.7 Hz, 1H), 7.17 (s, 1H), 7.09 (dd, J = 2.1, 9.0 Hz, 1H), 6.55 (d, J = 8.6 Hz, 1H), 6.11 (q, J = 6.6 Hz, 1H), 5.06 (dd, J = 5.3, 12.8 Hz, 1H), 4.44 (s, 2H), 4.18 (s, 4H), 4.13-4.02 (m, 4H), 3.12-3.01 (m, 2H), 2.95-2.82 (m, 1H), 2.65-2.52 (m, 3H), 2.07-1.97 (m, 1H), 1.83-1.68 (m, 5H), 1.58 (q, J = 11.1 Hz, 2H). Example 6.4-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-3- fluoro-2-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-1-piperidyl]-2-(2,6-dioxo-3- piperidyl)isoindoline-1,3-dione.

[0228] N,N-Diisopropylethylamine (180 µL, 1.02 mmol, 5.0 equiv) was added to a suspension of (R)-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-3-(5-fluoro-6-(2,6- diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1H-indazole (113 mg, 0.20 mmol, 1.0 equiv), hexafluorophosphate azabenzotriazole tetramethyluronium (93 mg, 0.25 mmol, 1.2 equiv), and 1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]piperidine-4-carboxylic acid HCl salt (95 mg, 0.20 mmol, 1.0 equiv) in N,N-dimethylacetamide (2.0 mL) at room temperature. The reaction was stirred at room temperature for 64 hours. The mixture was purified directly on a Biotage automated chromatography system (RediSep Gold C1830 g column), eluting with a gradient of 0 to 70% acetonitrile in water to give (50 mg). The compound was further purified on a Biotage automated chromatography system (RediSep Gold C1830 g column) eluting with a gradient of 0 to 45% acetonitrile in water to give a yellow solid (38 mg, 21%). LCMS m / z = 866.2(M+H); 1H NMR (400 MHz, DMSO-d6) δ = 13.12 (s, 1H), 11.07 (s, 1H), 8.57 (s, 2H), 8.38 (s, 1H), 7.76-7.66 (m, 2H), 7.47 (d, J = 9.0 Hz, 1H), 7.34 (t, J = 7.8 Hz, 2H), 7.20 (s, 1H), 7.10 (dd, J = 2.1, 9.0 Hz, 1H), 6.14 (q, J = 6.6 Hz, 1H), 5.10 (br dd, J = 5.4, 12.8 Hz, 1H), 4.44 (s, 2H), 4.32 (s, 4H), 4.10 (s, 2H), 3.72 (br d, J = 10.8 Hz, 2H), 3.00-2.83 - 96 -4896-4398-0599.1120039.000146 | TYRA.037PCT (m, 3H), 2.64-2.52 (m, 2H), 2.44 (br d, J = 7.1 Hz, 1H), 2.07-1.99 (m, 1H), 1.76 (br d, J = 6.6 Hz, 7H). Example 7.4-[4-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]-heptan-2-yl]sulfonyl]-1-piperidyl]-2-(2,6-dioxo-3- piperidyl)isoindoline-1,3-dione.

[0229] A mixture of 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-[2-(4- piperidylsulfonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]-1H-indazole (80 mg, 0.13 mmol, 1.0 equiv), 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (39 mg, 0.14 mmol, 1.1 equiv) and N,N-diisopropylethylamine (82 mg, 0.64 mmol, 5.0 equiv) in acetonitrile (3 mL) was heated at 80 °C for 16 hours. LCMS analysis indicated ~23% conversion to product. Additional 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (120 mg, 0.43 mmol, 3.4 equiv), N,N-diisopropylethylamine (246 mg, 0.64 mmol, 14.7 equiv) and acetonitrile (3 mL) were added. The reaction was continued to heat at 80 °C for 24 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dimethyl sulfoxide (5 mL) and purified on a Biotage automated chromatography system (RediSep Rf GOLD 100 g HP C18 column), eluting with a gradient of 0 to 100% acetonitrile (containing 0.1% vol / vol acetic acid) in water (containing 0.1% vol / vol acetic acid). The product containing fractions were combined (~100 mL), basified with 28% ammonium hydroxide solution (0.25 mL) to pH 8 and lyophilized to give a yellow solid (34 mg, 30%). LCMS m / z = 884.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ = 13.02 (br s, 1H), 11.08 (br s, 1H), 8.59 (s, 2H), 8.52 (d, J = 2.2 Hz, 1H), 7.87 (dd, J = 2.2, 8.6 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.46 (d, J = 9.0 Hz, 1H), 7.40- 7.34 (m, 2H), 7.17 (d, J = 2.0 Hz, 1H), 7.09 (dd, J = 2.2, 8.9 Hz, 1H), 6.54 (d, J = 8.7 Hz, 1H), 6.11 (q, J = 6.6 Hz, 1H), 5.11 (dd, J = 5.3, 12.9 Hz, 1H), 4.19 (s, 4H), 4.15 (s, 4H), 3.89- 3.61 (m, 4H), 3.04-2.82 (m, 4H), 2.65-2.53 (m, 2H), 2.11 (br d, J = 9.9 Hz, 2H), 2.07-2.01 (m, 1H), 1.76 (d, J = 6.6 Hz, 3H). Example 8.4-[4-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]heptan-2-yl]sulfonyl]-1-piperidyl]-2-(2,6-dioxo-3- piperidyl)isoindoline-1,3-dione - 97 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0230] Step 1. tert-Butyl (R)-4-((6-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H- indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)sulfonyl)piperidine-1-carboxylate. 1M Sodium bicarbonate (8.3 mL, 8.3 mmol, 8 equiv) was added to a solution of 3-[6-(2,6- diazaspiro[3.3]heptan-2-yl)-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H- indazole (0.5 g, 1.04 mmol, 1 equiv) in acetonitrile (60 mL), dichloromethane (60 mL) and water (50 mL) at 0 °C. After stirring for 10 minutes, tert-butyl 4-chlorosulfonylpiperidine-1- carboxylate (442 mg, 1.56 mmol, 1.5 equiv) was added and the mixture was stirred at 0 to 5 °C for 1 hour and then at room temperature for 16 hours. The layers were separated, and the aqueous layer was extracted with dichloromethane (100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (Yamazen 55g silica gel column), eluting with a gradient of 0 to 100% ethyl acetate in hexanes to give an off-white solid (360 mg, 48%). LCMS m / z = 728.2 (M+H).

[0231] Step 2. (R)-5-(1-(3,5-Dichloropyridin-4-yl)ethoxy)-3-(6-(6-(piperidin-4- ylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1H-indazole. Trifluoroacetic acid (3 mL) was added to a solution of tert-butyl (R)-4-((6-(5-(5-(1-(3,5-dichloropyridin-4- yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)sulfonyl)piperidine- 1-carboxylate (360 mg, 0.49 mmol, 1.0 equiv) in dichloromethane (3 mL) at room temperature, and the mixture was stirred at room temperature for 16 hours. LCMS analysis indicated that the reaction was complete. The mixture was concentrated under reduced pressure, diluted with ethyl acetate (20 mL), then treated with 3M sodium hydroxide solution (6 mL). The layers were separated, and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in dimethyl sulfoxide (5 mL) and purified on a Biotage automated chromatography system (RediSep Rf GOLD 100 g HP C18 column), eluting with a gradient of 0 to 100% acetonitrile in water. The - 98 -4896-4398-0599.1120039.000146 | TYRA.037PCT product containing fractions were combined and lyophilized to give an off-white solid (250 mg, 81%). LCMS m / z = 628.1 (M+H).

[0232] Step 3.4-[4-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol- 3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]heptan-2-yl]sulfonyl]-1-piperidyl]-2-(2,6-dioxo-3- piperidyl)isoindoline-1,3-dione. N,N-Diisopropylethylamine (165 mg, 1.3 mmol, 10 equiv) and hexafluorophosphate azabenzotriazole tetramethyluronium (145 mg, 0.38 mmol, 3.0 equiv) were sequentially added at 0 °C to a mixture of (R)-5-(1-(3,5-Dichloropyridin-4- yl)ethoxy)-3-(6-(6-(piperidin-4-ylsulfonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-yl)-1H- indazole (80 mg, 0.13 mmol, 1.0 equiv) and 2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo- isoindolin-4-yl]amino]acetic acid (42 mg, 0.13 mmol, 1.0 equiv) in N,N-dimethylformamide (4 mL). The reaction stirred at 0 ºC for 1 hour and room temperature for 16 hours. The reaction mixture was purified on a Biotage automated chromatography system (RediSep Rf GOLD 100 g HP C18 column), eluting with a gradient of 0 to 100% acetonitrile (containing 0.1% vol / vol acetic acid) in water (containing 0.1% vol / vol acetic acid). The product containing fractions were combined (~ 50 mL), basified with 28% ammonium hydroxide solution (0.13 mL) to pH 8 and lyophilized to give a yellow solid (7 mg, 6%, 93% purity). LCMS m / z = 941.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ = 13.00 (br s, 1H), 11.08 (br s, 1H), 8.59 (s, 2H), 8.52 (s, 1H), 7.87 (dd, J = 2.0, 8.5 Hz, 1H), 7.62 (t, J = 7.7 Hz, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.18-7.04 (m, 5H), 6.54 (d, J = 8.7 Hz, 1H), 6.11 (q, J = 6.6 Hz, 1H), 5.07 (dd, J = 5.3, 12.8 Hz, 1H), 4.51 (br d, J = 12.1 Hz, 1H), 4.32-4.24 (m, 1H), 4.21-4.11 (m, 9H), 4.01 (br d, J = 12.8 Hz, 1H), 3.45 (br t, J = 11.8 Hz, 1H), 3.12 (br t, J = 12.3 Hz, 1H), 2.93- 2.84 (m, 1H), 2.73 (br t, J = 12.0 Hz, 1H), 2.62-2.56 (m, 1H), 2.54 (s, 1H), 2.09-2.00 (m, 3H), 1.76 (d, J = 6.6 Hz, 3H), 1.68 (br d, J = 9.5 Hz, 1H), 1.52-1.43 (m, 1H). Example 9. 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2- [4-[1-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]acetyl]piperidine-4- carbonyl]piperazin-1-yl]pyridine-3-carbonitrile - 99 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0233] N,N-Diisopropylethylamine (80 µL, 0.45 mmol, 5 equiv) was added to a suspension of 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2- [4-(piperidine-4-carbonyl)piperazin-1-yl]pyridine-3-carbonitrile (61 mg, 91 µmol, 1 equiv), hexafluorophosphate azabenzotriazole tetramethyluronium (41 mg, 0.1 mmol, 1.2 equiv) and 2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]acetic acid (50 mg, 91 µmol, 1 equiv) in N,N-dimethylacetamide (1 mL). After stirring at room temperature for 5 hours, the resulting crude mixture was purified directly on a Biotage automated chromatography system (RediSep Gold C1830 g column) eluting with a gradient of 0 to 70% acetonitrile in water to give a yellow solid (16 mg, 18%). LCMS m / z = 948.2 (M+H); 1H NMR (400 MHz, DMSO- d6) δ = 13.05 (br s, 1H), 11.09 (br s, 1H), 8.82 (d, J = 2.1 Hz, 1H), 8.59 (s, 2H), 8.24 (d, J = 2.1 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.14-7.06 (m, 4H), 7.03 (s, 1H), 6.01 (q, J = 6.7 Hz, 1H), 5.07 (br dd, J = 5.3, 12.9 Hz, 1H), 4.42 (br d, J = 11.9 Hz, 1H), 4.30-4.14 (m, 2H), 3.94 (br d, J = 12.2 Hz, 1H), 3.87 (s, 3H), 3.79 (br s, 4H), 3.69 (br d, J = 9.8 Hz, 4H), 3.20-3.11 (m, 1H), 3.07-2.99 (m, 1H), 2.94-2.76 (m, 2H), 2.67-2.56 (m, 2H), 2.07-2.00 (m, 1H), 1.81- 1.71 (m, 5H), 1.63 (br d, J = 10.6 Hz, 1H), 1.45 (br d, J = 9.4 Hz, 1H). Example 10.5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2- [4-[1-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]acetyl]piperidine-4- carbonyl]piperazin-1-yl]pyridine-3-carbonitrile. - 100 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0234] N,N-Diisopropylethylamine (100 µL, 0.56 mmol, 5 equiv) was added to a suspension of 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2- [4-(piperidine-4-carbonyl)piperazin-1-yl]pyridine-3-carbonitrile (71 mg, 0.11 mmol, 1 equiv), hexafluorophosphate azabenzotriazole tetramethyluronium (50 mg, 0.13 mmol, 1.2 equiv) and 2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]acetic acid (62 mg, 0.11 mmol, 1 equiv) in N,N-dimethylacetamide (1 mL) at room temperature. After stirring at room temperature for 17 hours, the resulting crude mixture was purified directly on a Biotage automated chromatography system (RediSep Gold C1830 g column), eluting with a gradient of 0 to 70% acetonitrile in water to give a yellow solid (20 mg, 17%). LCMS m / z = 948.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ = 13.05 (br s, 1H), 11.05 (br s, 1H), 8.82 (d, J = 2.3 Hz, 1H), 8.59 (s, 2H), 8.24 (d, J = 2.4 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.16-6.98 (m, 5H), 6.01 (q, J = 6.7 Hz, 1H), 5.04 (dd, J = 5.4, 12.8 Hz, 1H), 4.40 (br d, J = 12.8 Hz, 1H), 4.22-4.08 (m, 2H), 3.98 (br d, J = 12.5 Hz, 1H), 3.86 (s, 3H), 3.79 (br s, 4H), 3.69 (br d, J = 9.2 Hz, 4H), 3.15 (br t, J = 12.0 Hz, 1H), 3.02 (br t, J = 10.7 Hz, 1H), 2.93-2.83 (m, 1H), 2.77 (br t, J = 12.0 Hz, 1H), 2.61-2.53 (m, 2H), 2.04-1.96 (m, 1H), 1.77 (d, J = 6.6 Hz, 4H), 1.73 (br s, 1H), 1.69-1.58 (m, 1H), 1.49-1.38 (m, 1H). Example 11.5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2- [4-[1-[4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]butanoyl]piperidine- 4-carbonyl]piperazin-1-yl]pyridine-3-carbonitrile.

[0235] N,N-Diisopropylethylamine (80 µL, 0.45 mmol, 5.0 equiv) was added to a suspension of 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2- [4-(piperidine-4-carbonyl)piperazin-1-yl]pyridine-3-carbonitrile (57 mg, 90 µmol, 1 equiv), - 101 -4896-4398-0599.1120039.000146 | TYRA.037PCT hexafluorophosphate azabenzotriazole tetramethyluronium (40 mg, 0.1 mmol, 1.2 equiv) and 4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]butanoic acid (50 mg, 90 µmol, 1 equiv) in N,N-dimethylacetamide (1 mL). After stirring at room temperature for 17 hours, the resulting crude mixture was purified directly on a Biotage automated chromatography system (RediSep Gold C1830 g column), eluting with a gradient of 0 to 70% acetonitrile in water to give a yellow solid (4 mg, 4% yield). LCMS m / z = 976.3 (M+H); 1H NMR (400 MHz, DMSO-d6) δ = 13.05 (s, 1H), 11.08 (s, 1H), 8.81 (d, J = 2.3 Hz, 1H), 8.59 (s, 2H), 8.24 (d, J = 2.3 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.18 (d, J = 8.7 Hz, 1H), 7.09 (s, 1H), 7.02 (t, J = 3.5 Hz, 2H), 6.67 (t, J = 6.2 Hz, 1H), 6.00 (q, J = 6.7 Hz, 1H), 5.05 (dd, J = 5.3, 12.9 Hz, 1H), 4.42 (br d, J = 11.6 Hz, 1H), 3.91-3.84 (m, 4H), 3.77 (br s, 4H), 3.68 (br d, J = 11.1 Hz, 4H), 3.14-2.82 (m, 4H), 2.67-2.53 (m, 3H), 2.42 (q, J = 6.7 Hz, 2H), 2.06-2.00 (m, 1H), 1.87-1.65 (m, 8H), 1.57-1.46 (m, 1H), 1.45-1.33 (m, 1H). Example 12.4-[[4-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]- 2-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-1-piperidyl]-4-oxo-butyl]amino]-2- (2,6-dioxo-3-piperidyl)isoindoline-1,3-dione.

[0236] Step 1. tert-Butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)butanoate. A mixture of 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (0.5 g, 1.81 mmol, 1 equiv), tert-butyl 4-aminobutanoate (354 mg, 1.81 mmol, 1 equiv) and - 102 -4896-4398-0599.1120039.000146 | TYRA.037PCT N,N-diisopropylethylamine (3.15 mL, 18.1 mmol, 10 equiv) in dimethylsulfoxide (5 mL) was stirred at 80 °C for 16 hours. The mixture was poured into water (40 mL) and was extracted with ethyl acetate (3 x 40 mL). The combined organic layers were washed with saturated brine (2 x 30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (Biotage Sfar HC 10 g column), eluting with a gradient of 0 to 50% ethyl acetate in hexanes to give a green solid (270 mg, 35%). LCMS m / z = 438.1 (M+Na).

[0237] Step 2.4-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)butanoic acid.4M HCl in 1,4-dioxane (4.6 mL, 18.5 mmol, 30 equiv) was added to a suspension of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)butanoate (270 mg, 0.62 mmol, 1 equiv) in 1,4-dioxane (1.35 mL), and the resulting mixture was stirred at 50 °C for 16 hours. After cooling to room temperature, the volatiles were evaporated under reduced pressure and the residue was dried under vacuum at 35 °C for 1 hour to give a brown oil (358 mg, >100% yield). This material was used directly in the next step. LCMS m / z = 360.1 (M+H).

[0238] Step 3. tert-Butyl 1-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)butanoyl)piperidine-4-carboxylate. N,N-Diisopropylethylamine (0.44 mL, 2.5 mmol, 5 equiv) was added to a suspension of 4-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)butanoic acid (358 mg, 0.5 mmol, 1 equiv), hexafluorophosphate azabenzotriazole tetramethyluronium (230 mg, 0.6 mmol, 1.2 equiv), and tert-butyl piperidine-4-carboxylate (92 mg, 0.5 mmol, 1 equiv) in N,N-dimethylacetamide (5 mL) at room temperature. After stirring at room temperature for 16 hours, the mixture was diluted with water (30 mL) and extracted with MTBE (3 x 30 mL). The combined organic layers were washed sequentially with water (100 mL) and saturated brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (Biotage Sfar HC10 g column), eluting with a gradient of 0 to 100% ethyl acetate in hexanes to give a yellow solid (140 mg, 42% yield over 2 steps). LCMS m / z = 527.2 (M+H).

[0239] Step 4.1-(4-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)butanoyl)piperidine-4-carboxylic acid.4M HCl in 1,4-dioxane (1.95 mL, 7.8 mmol, 30 equiv) was added to a suspension of tert-butyl 1-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)butanoyl)piperidine-4-carboxylate (140 mg, 0.26 mmol, 1 equiv) - 103 -4896-4398-0599.1120039.000146 | TYRA.037PCT in 1,4-dioxane (0.7 mL, and the resulting mixture was stirred at 50 °C for 8 hours. After cooling to room temperature, the volatiles were evaporated under reduced pressure and dried under vacuum at 40 °C for 1.5 hours to give a brown solid (180 mg), which was used directly in the next step. LCMS m / z = 471.2 (M+H).

[0240] Step 5.4-[[4-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H- indazol-3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-1-piperidyl]-4-oxo- butyl]amino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione. N,N-Diisopropylethylamine (220 µL, 1.24 mmol, 5 equiv) was added to a suspension of 1-(4-((2-(2,6-Dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4-yl)amino)butanoyl)piperidine-4-carboxylic acid (180 mg, 0.25 mmol, 1 equiv), hexafluorophosphate azabenzotriazole tetramethyluronium (114 mg, 0.3 mmol, 1.2 equiv), and 3-[6-(2,6-diazaspiro[3.3]heptan-2-yl)-3-pyridyl]-5-[(1R)-1-(3,5- dichloro-4-pyridyl)ethoxy]-1H-indazole (120 mg, 0.25 mmol, 1 equiv) in N,N- dimethylacetamide (2.5 mL) at room temperature. After stirring at room temperature for 18 hours, the mixture was diluted with water (20 mL) and extracted with 5% methanol in dichloromethane (3 x 20 mL). The combined organic layers were washed sequentially with water (50 mL) and saturated brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (RediSep Gold C1830 g column), eluting with a gradient of 0 to 70% acetonitrile in water to give a yellow solid (25 mg, 11% yield). LCMS m / z = 933.3 (M+H); 1H NMR (400 MHz, DMSO-d6) δ = 13.00 (br s, 1H), 11.08 (br s, 1H), 8.59 (s, 2H), 8.52 (d, J = 2.1 Hz, 1H), 7.87 (dd, J = 2.3, 8.6 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.21-7.14 (m, 2H), 7.09 (dd, J = 2.1, 9.0 Hz, 1H), 7.02 (d, J = 7.1 Hz, 1H), 6.67 (t, J = 6.1 Hz, 1H), 6.54 (d, J = 8.6 Hz, 1H), 6.11 (q, J = 6.7 Hz, 1H), 5.05 (dd, J = 5.4, 12.9 Hz, 1H), 4.45-4.34 (m, 3H), 4.17 (s, 4H), 4.07 (s, 2H), 3.86 (br d, J = 12.8 Hz, 1H), 3.35 (br s, 2H), 3.04 (br t, J = 12.0 Hz, 1H), 2.95-2.82 (m, 1H), 2.69-2.53 (m, 3H), 2.48-2.31 (m, 3H), 2.07-1.98 (m, 1H), 1.83-1.73 (m, 5H), 1.66 (br d, J = 11.1 Hz, 2H), 1.53-1.38 (m, 1H), 1.37- 1.26 (m, 1H). Example 13.5-[[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]- 2-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-1-piperidyl]-2-oxo-ethyl]amino]-2- (2,6-dioxo-3-piperidyl)isoindoline-1,3-dione. - 104 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0241] Step 1. tert-Butyl (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)glycinate. A mixture of 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (1.0 g, 1 equiv, 3.62 mmol), tert-butyl 2-aminoacetate (475 mg, 3.62 mmol, 1 equiv) and N,N- diisopropylethylamine (1.9 mL, 10.86 mmol, 3 equiv) in dimethylsulfoxide (5 mL) was stirred at 80 °C for 21 hours. The mixture was cooled to room temperature, poured into water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with saturated brine (2 x 100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (Biotage Sfar HC 10 g column) eluting with a gradient of 0 to 50% ethyl acetate in hexanes to give a green solid (215 mg, 15%). LCMS m / z = 388 (M+H).

[0242] Step 2. (2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycine. tert- Butyl (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycinate (220 mg, 0.54 mmol, 1 equiv) as a suspension in 1,4-dioxane (1.3 mL) was treated at room temperature with 4M HCl in 1,4-dioxane (4.05 mL, 16.2 mmol, 30 equiv) and the mixture was stirred at 50 °C for 17 hours. After cooling to room temperature, the volatiles were evaporated under reduced pressure and the residue was dried under vacuum at 40 °C for 2 hours to give crude a dark- orange, thick oil (412 mg, >100% yield), which was used directly in the next step. LCMS m / z = 332.1 (M+H).

[0243] Step 3. tert-Butyl 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)glycyl)piperidine-4-carboxylate. N,N-Diisopropylethylamine (420 µL, 2.38 mmol, 5 equiv) was added to a suspension of (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)glycine (350 mg, 0.48 mmol, 1 equiv), hexafluorophosphate azabenzotriazole tetramethyluronium (217 mg, 0.57 mmol, 1.2 equiv) and tert-butyl piperidine-4-carboxylate (88 mg, 0.48 mmol, 1 equiv) in N,N-dimethylacetamide (5 mL) at room temperature. After - 105 -4896-4398-0599.1120039.000146 | TYRA.037PCT stirring at room temperature for 16 hours, the mixture was diluted with water (30 mL) and extracted with MTBE (3 x 30 mL). The combined organic layers were washed sequentially with water (100 mL) and saturated brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (Biotage Sfar HC 10 g column), eluting with a gradient of 0 to 100% acetonitrile in water to give a dark-yellow solid (150 mg, 50% yield over 2 steps). LCMS m / z= 521.2 (M+Na).

[0244] Step 4.1-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)glycyl)piperidine-4-carboxylic acid.4M HCl in 1,4-dioxane (2.03 mL, 8.12 mmol, 30 equiv) was added to a suspension of tert-butyl 1-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)glycyl)piperidine-4-carboxylate (150 mg, 0.27 mmol, 1 equiv) in 1,4- dioxane (0.75 mL) and the mixture was stirred at 50 °C for 15 hours. After cooling to room temperature, the volatiles were evaporated under reduced pressure and the residue was dried under vacuum at 40 °C for 2 hours to give a dark-orange solid (175 mg, >100% yield), which was used directly in the next step. LCMS m / z = 443.1 (M+H).

[0245] Step 5.5-((2-(4-(6-(5-(5-((R)-1-(3,5-Dichloropyridin-4-yl)ethoxy)-1H- indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)piperidin-1-yl)-2- oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. N,N- Diisopropylethylamine (250 µL, 1.4 mmol, 5 equiv) was added to a suspension of 1-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperidine-4-carboxylic acid (175 mg, 0.28 mmol, 1 equiv), hexafluorophosphate azabenzotriazole tetramethyluronium (128 mg, 0.34 mmol, 1.2 equiv) and 3-[6-(2,6-diazaspiro[3.3]heptan-2-yl)-3-pyridyl]-5-[(1R)-1-(3,5- dichloro-4-pyridyl)ethoxy]-1H-indazole (150 mg, 0.28 mmol, 1 equiv) in N,N- dimethylacetamide (2.8 mL) at room temperature. After stirring at room temperature for 18 hours, the mixture was diluted with water (20 mL) and extracted with 5% methanol in dichloromethane (3 x 20 mL). The combined organic layers were washed sequentially with water (50 mL) and saturated brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (RediSep Gold C1830 g column), eluting with a gradient of 0 to 70% acetonitrile in water to give a yellow solid (6 mg, 2% yield). LCMS m / z = 905.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ = 12.99 (s, 1H), 11.05 (s, 1H), 8.59 (s, 2H), 8.52 (s, 1H), 7.87 (dd, J = 2.0, 8.6 Hz, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.46 (d, J = 9.0 Hz, 1H), 7.17 - 106 -4896-4398-0599.1120039.000146 | TYRA.037PCT (s, 1H), 7.14-7.07 (m, 2H), 7.02 (br d, J = 8.4 Hz, 1H), 6.55 (br d, J = 8.7 Hz, 1H), 6.11 (q, J = 6.6 Hz, 1H), 5.04 (br dd, J = 5.3, 12.9 Hz, 1H), 4.47-4.41 (m, 2H), 4.35 (br s, 1H), 4.22- 4.11 (m, 6H), 4.09 (s, 2H), 3.96 (br d, J = 13.9 Hz, 1H), 3.74-3.64 (m, 1H), 3.28 (s, 1H), 3.11 (br t, J = 12.3 Hz, 1H), 2.89-2.83 (m, 1H), 2.79-2.69 (m, 1H), 2.58 (br d, J = 16.6 Hz, 2H), 2.04-1.97 (m, 1H), 1.76 (d, J = 6.6 Hz, 3H), 1.70 (br d, J = 11.4 Hz, 2H), 1.61-1.53 (m, 1H), 1.37 (br d, J = 11.4 Hz, 1H). Example 14.4-[[4-[4-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]- 2-pyridyl]-2,6-diazaspiro[3.3]heptan-2-yl]sulfonyl]-1-piperidyl]-4-oxo-butyl]amino]-2- (2,6-dioxo-3-piperidyl)isoindoline-1,3-dione.

[0246] Triethylamine (0.05 mL, 0.32 mmol, 4.0 equiv) and 50 wt% propylphosphonic anhydride in ethyl acetate solution (0.1 mL, 0.16 mmol, 2.0 equiv) were sequentially added to a solution of 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-[2-(4- piperidylsulfonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]-1H-indazole (50 mg, 0.08 mmol, 1.0 equiv) and 4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]butanoic acid (29 mg, 0.08 mmol, 1.0 equiv) in N,N-dimethylformamide (5 mL) at room temperature. The mixture was stirred at room temperature for 16 hours. The reaction mixture was directly purified on a Biotage automated chromatography system (RediSep Rf GOLD 100 g HP C18 column) eluting with a gradient of 0 to 100% acetonitrile (w / 0.1% vol / vol acetic acid) in water (w / 0.1% vol / vol acetic acid). The product containing fractions were combined (approximately 42 mL), basified with 28% ammonium hydroxide solution (0.1 mL) to pH 8 and lyophilized to give an off-white solid (6 mg, 8%). LCMS m / z = 969.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ = 13.03 (br s, 1H), 11.03 (br s, 1H), 8.59 (s, 2H), 8.51 (d, J = 2.0 Hz, 1H), 7.87 (dd, J = 2.2, 8.6 Hz, 1H), 7.62-7.56 (m, 1H), 7.46 (d, J = 9.0 Hz, 1H), 7.20-7.12 (m, 2H), 7.09 (dd, J = 2.1, 8.9 Hz, 1H), 7.02 (d, J = 7.1 Hz, 1H), 6.70-6.64 (m, 1H), 6.54 (d, J = 8.7 Hz, 1H), 6.11 (q, J = 6.6 Hz, 1H), 5.05 (dd, J = 5.3, 12.8 Hz, 1H), 4.52 (br d, J = 12.7 Hz, 1H), 4.30-4.26 (m, 1H), 4.17 (s, 3H), 4.16-4.13 (m, 1H), 4.11 (s, 3H), 3.97 (br d, J = 13.3 Hz, 1H), 3.84-3.79 (m, 1H), 3.70-3.62 (m, 1H), 3.43-3.35 (m, 2H), 3.10-3.00 (m, 1H), 2.93- 2.84 (m, 1H), 2.62-2.53 (m, 3H), 2.47-2.38 (m, 3H), 2.05-1.97 (m, 3H), 1.84-1.78 (m, 2H), 1.78-1.74 (m, 4H), 1.59-1.47 (m, 1H), 1.46-1.35 (m, 1H). Example 15.4-[[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]- 2-pyridyl]-2,6-diazaspiro[3.3]-heptane-2-carbonyl]-1-piperidyl]-2-oxo-ethyl]amino]-2- (2,6-dioxo-3-piperidyl)-isoindoline-1,3-dione. - 107 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0247] Step 1. tert-Butyl (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)glycinate. A mixture of 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (1.0 g, 3.62 mmol, 1 equiv), tert-butyl 2-aminoacetate (712 mg, 5.43 mmol, 1.5 equiv), and N,N- diisopropylethylamine (6.3 mL, 36.2 mmol, 10 equiv) in dimethylsulfoxide (10 mL) was stirred at 80 °C for 16 hours. The mixture was cooled to room temperature, poured into water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with saturated brine (2 x 50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (Biotage Sfar HC 25 g column), eluting with a gradient of 0 to 50% ethyl acetate in hexanes to give a yellow solid (550 mg, 37%). LCMS m / z = 410.1 (M+Na).

[0248] Step 2. (2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycine.4M HCl in 1,4-dioxane (10.6 mL, 42.6 mmol, 30 equiv) was added to a suspension of tert-butyl (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycinate (550 mg, 1.42 mmol, 1 equiv) in 1,4-dioxane (2.75 mL), and the resulting mixture was stirred at 50 °C for 18 hours. After cooling to room temperature, the volatiles were evaporated under reduced pressure and the residue was dried under vacuum at 40 °C for 2 hours to give a dark-orange thick oil (530 mg, >100% yield), which was used directly in the next step. LCMS m / z = 332.1 (M+H).

[0249] Step 3. tert-Butyl 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)glycyl)piperidine-4-carboxylate. N,N-Diisopropylethylamine (0.62 mL, 3.5 mmol, 5 equiv) was added to a suspension of crude (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin- 4-yl) (390 mg, 0.7 mmol, 1 equiv), hexafluorophosphate azabenzotriazole tetramethyluronium (323 mg, 0.85 mmol, 1.2 equiv), and tert-butyl piperidine-4-carboxylate (131 mg, 0.7 mmol, 1 equiv) in N,N-dimethylacetamide (7.5 mL) at room temperature. After - 108 -4896-4398-0599.1120039.000146 | TYRA.037PCT stirring at room temperature for 16 hours, the mixture was diluted with water (30 mL) and extracted with MTBE (3 x 30 mL). The combined organic layers were washed sequentially with water (100 mL) and saturated brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (Biotage Sfar HC 10 g column), eluting with a gradient of 0 to 100% ethyl acetate in hexanes to give a yellow solid (195 mg, 37% yield over 2 steps). LCMS m / z= 499.2 (M+H).

[0250] Step 4.1-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)glycyl)piperidine-4-carboxylic acid.4M HCl in 1,4-dioxane (3.18 mL, 12.7 mmol, 30 equiv) was added to a suspension of tert-butyl 1-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)glycyl)piperidine-4-carboxylate (218 mg, 0.42 mmol, 1 equiv) in 1,4- dioxane (1.1 mL), and the resulting mixture was stirred at 50 °C for 17 hours. After cooling to room temperature, the volatiles were evaporated under reduced pressure and dried under vacuum at 40 °C for 2 hours to give a dark-orange solid (41 mg, 20%), which was used directly in the next step. LCMS m / z = 443.1 (M+H).

[0251] Step 5.4-[[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H- indazol-3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]-heptane-2-carbonyl]-1-piperidyl]-2-oxo- ethyl]amino]-2-(2,6-dioxo-3-piperidyl)-isoindoline-1,3-dione. N,N-diisopropylethylamine (75 µL, 0.42 mmol, 5 equiv) was added to a suspension of 1-((2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4-yl)glycyl)piperidine-4-carboxylic acid (41 mg, 83 µmol, 1 equiv), hexafluorophosphate azabenzotriazole tetramethyluronium (38 mg, 0.1 mmol, 1.2 equiv), and 3-[6-(2,6-diazaspiro[3.3]heptan-2-yl)-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]- 1H-indazole (45 mg, 83 µmol, 1 equiv) in N,N-dimethylacetamide (0.9 mL) at room temperature. After stirring at room temperature for 18 hours, the mixture was diluted with water (20 mL) and extracted with 5% methanol in dichloromethane (3 x 20 mL). The combined organic layers were washed sequentially with water (50 mL) and saturated brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (RediSep Gold C1830 g column) eluting with a gradient of 0 to 70% acetonitrile in water to give a yellow solid (6 mg, 8% yield). LCMS m / z = 905.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ = 13.00 (s, 1H), 11.09 (s, 1H), 8.59 (s, 2H), 8.52 (d, J = 2.0 Hz, 1H), 7.87 (dd, J = 2.1, 8.6 Hz, 1H), 7.61 (t, J = 7.3 Hz, 1H), 7.46 (d, J = 9.0 Hz, 1H), 7.17 (s, 1H), 7.14-7.05 (m, 4H), 6.57-6.51 (m, - 109 -4896-4398-0599.1120039.000146 | TYRA.037PCT 1H), 6.11 (q, J = 6.7 Hz, 1H), 5.07 (dd, J = 5.4, 12.8 Hz, 1H), 4.44 (s, 2H), 4.37 (br d, J = 12.3 Hz, 1H), 4.28-4.14 (m, 6H), 4.09 (s, 2H), 3.91 (br d, J = 12.1 Hz, 1H), 3.16-3.07 (m, 1H), 2.95-2.85 (m, 1H), 2.77 (br t, J = 11.6 Hz, 1H), 2.63-2.53 (m, 3H), 2.07-2.00 (m, 1H), 1.76 (d, J = 6.6 Hz, 3H), 1.71 (br d, J = 10.9 Hz, 2H), 1.62-1.51 (m, 1H), 1.45-1.34 (m, 1H). Example 16.4-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]-heptane-2-carbonyl]-piperazin-1-yl]-2-(2,6-dioxo-3- piperidyl)isoindoline-1,3-dione. Step 4 Example 16 Step 1 Step 2 Step 3

[0252] Step 1.1-(tert-Butyl) 4-(4-nitrophenyl) piperazine-1,4-dicarboxylate. A mixture of tert-butyl piperazine-1-carboxylate (500 mg, 2.6 mmol, 1.0 equiv), 4- nitrophenylchloroformate (541.0 mg, 2.6 mmol, 1.0 equiv) and triethylamine (0.4 mL, 2.6 mmol, 1.0 equiv) in dichloromethane (25.0 mL) was stirred at room temperature for 6 hours. The reaction mixture was absorbed onto silica gel (12 g) under reduced pressure. The residue was purified on a Biotage automated chromatography system (Biotage Sfar 25 g, 20 µm silica gel), eluting with a gradient of 0 to 50% ethyl acetate in hexanes to give a white solid (0.70 g, 74%). LCMS m / z = 375 (M+Na).

[0253] Step 2. tert-Butyl (R)-4-(6-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H- indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)piperazine-1-carboxylate. A mixture of 1-(tert-butyl) 4-(4-nitrophenyl) piperazine-1,4-dicarboxylate (73 mg, 0.2 mmol, 1.0 equiv)) and 3-[6-(2,6-diazaspiro[3.3]heptan-2-yl)-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-4- pyridyl)ethoxy]-1H-indazole (100 mg, 0.2 mmol, 1.0 equiv) in dioxane (1.0 mL) was stirred at room temperature. N,N-Diisopropylethylamine (0.1 mL, 0.6 mmol, 3.0 equiv) was added and the reaction mixture was stirred at 90 °C for 24 hours. The reaction mixture was cooled - 110 - 4896-4398-0599.1120039.000146 | TYRA.037PCT to room temperature and concentrated under reduced pressure onto Celite (1g). The residue was purified on a Biotage automated chromatography system (Biotage Amino Duo column 5 g, 50 µm silica gel), eluting with a gradient of 5 to 25% methanol in ethyl acetate to give a white solid (38 mg, 26% yield). LCMS m / z = 693, 695 (M+H).

[0254] Step 3. (R)-(6-(5-(5-(1-(3,5-Dichloropyridin-4-yl)ethoxy)-1H-indazol-3- yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)(piperazin-1-yl)methanone bis(trifluoroacetic acid) salt. A mixture of tert-butyl (R)-4-(6-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H- indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)piperazine-1-carboxylate (38.0 mg, 0.06 mmol, 1.0 equiv) and trifluoroacetic acid (0.3 mL, 4.4 mmol, 80 equiv) in dichloromethane (0.3 mL) was stirred at room temperature for 14 hours. The solvent was removed under reduced pressure. Dichloromethane (1.0 mL) was added, and the solvent was removed under reduced pressure to give a brown oil (46 mg, 100%), which was used directly in the next step. LCMS m / z = 593, 595 (M+H, free base).

[0255] Step 4.4-(4-(6-(5-(5-((R)-1-(3,5-Dichloropyridin-4-yl)ethoxy)-1H-indazol- 3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)piperazin-1-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione. N,N-Diisopropylethylamine (0.31 mL, 1.8 mmol, 30.0 equiv) was added to a mixture of (R)-(6-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H- indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)(piperazin-1-yl)methanone bis(trifluoroacetic acid) salt (48.3 mg, 0.06 mmol, 1.0 equiv) and 2-(2,6-dioxo-3-piperidyl)-4- fluoro-isoindoline-1,3-dione (18.0 mg, 0.06 mmol, 1.1 equiv) in dimethyl sulfoxide (1.0 mL). The reaction mixture was heated to 80 °C under a nitrogen atmosphere, stirred for 22 hours then cooled to room temperature. The reaction mixture was directly purified on a Biotage automated chromatography system (RediSep Gold C18 column, 15.5 g) eluting with a gradient of 0 to 100% acetonitrile in water to give a white solid (12 mg, 15% yield). LCMS m / z = 849, 851 (M+H); 1H NMR (400 MHz, DMSO-d6) δ = 12.99 (s, 1H), 11.08 (br s, 1H), 8.59 (s, 2H), 8.52 (s, 1H), 7.87 (br d, J = 8.7 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.40 (br d, J = 7.2 Hz, 1H), 7.36 (br d, J = 8.6 Hz, 1H), 7.17 (s, 1H), 7.09 (br d, J = 9.0 Hz, 1H), 6.57-6.50 (m, 1H), 6.11 (q, J = 6.6 Hz, 1H), 5.11 (dd, J = 5.4, 12.8 Hz, 1H), 4.17 (br d, J = 8.6 Hz, 8H), 3.53-3.43 (m, 4H), 3.29 (br s, 4H), 2.95-2.82 (m, 1H), 2.65-2.53 (m, 2H), 2.08-1.99 (m, 1H), 1.76 (d, J = 6.6 Hz, 3H). - 111 -4896-4398-0599.1120039.000146 | TYRA.037PCT Example 17.5-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]-heptane-2-carbonyl]-piperazin-1-yl]-2-(2,6-dioxo-3- piperidyl)-isoindoline-1,3-dione

[0256] 5-(4-(6-(5-(5-((R)-1-(3,5-Dichloropyridin-4-yl)ethoxy)-1H-indazol-3- yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)piperazin-1-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione. N,N-Diisopropylethylamine (0.50 mL, 2.8 mmol, 30.0 equiv) was added to a mixture of crude [6-[5-[5-[(1R)-1-(3,5-dichloro-4- pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]heptan-2-yl]-piperazin-1-yl- methanone di-TFA salt(77 mg, 0.09 mmol, 1.0 equiv) and 2-(2,6-dioxo-3-piperidyl)-5-fluoro- isoindoline-1,3-dione (29.0 mg, 0.10 mmol, 1.1 equiv) in dimethyl sulfoxide (1.0 mL). The reaction mixture was heated to 80 °C under a nitrogen atmosphere for 22 hours then cooled to room temperature. The reaction mixture was directly purified on a Biotage automated chromatography system (RediSep Gold C18 column, 15.5 g), eluting with a gradient of 0 to 100% acetonitrile in water to give a white solid (11.4 mg, 15% yield). LCMS m / z = 849, 851 (M+H); 1H NMR (400 MHz, DMSO-d6) δ = 13.01 (br s, 1H), 11.07 (br s, 1H), 8.59 (s, 2H), 8.52 (d, J = 2.0 Hz, 1H), 7.86 (dd, J = 2.2, 8.6 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.38-7.30 (m, 1H), 7.25 (dd, J = 2.0, 8.7 Hz, 1H), 7.19-7.14 (m, 1H), 7.09 (dd, J = 2.1, 9.0 Hz, 1H), 6.54 (d, J = 8.7 Hz, 1H), 6.11 (q, J = 6.6 Hz, 1H), 5.07 (dd, J = 5.3, 12.9 Hz, 1H), 4.17 (br d, J = 5.0 Hz, 8H), 3.60-3.38 (m, 8H), 2.95-2.82 (m, 1H), 2.65-2.53 (m, 2H), 2.08-1.97 (m, 1H), 1.76 (d, J = 6.6 Hz, 3H). Example 18.5-[[4-[4-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]- 2-pyridyl]-2,6-diazaspiro[3.3]-heptan-2-yl]sulfonyl]-1-piperidyl]-4-oxo-butyl]amino]-2- (2,6-dioxo-3-piperidyl)-isoindoline-1,3-dione. - 112 -4896-4398-0599.1120039.000146 | TYRA.037PCT Step 3 Step 1 Step 2 Example 18

[0257] Step 1. tert-Butyl (R)-(4-(4-((6-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)- 1H-indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)sulfonyl)piperidin-1-yl)-4- oxobutyl)carbamate. Triethylamine (0.09 mL, 0.64 mmol, 4.0 equiv) and 50 wt.% propylphosphonic anhydride in ethyl acetate solution (0.19 mL, 0.32 mmol, 2.0 equiv) were sequentially added to a solution of 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-[2-(4- piperidylsulfonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]-1H-indazole (100 mg, 0.16 mmol, 1.0 equiv) and 4-(tert-butoxycarbonyl-amino)butanoic acid (33 mg, 0.16 mmol, 1.0 equiv) in N,N-dimethylformamide (10 mL) at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was purified on a Biotage automated chromatography system (RediSep Rf GOLD 100 g HP C18 column), eluting with a gradient of 0 to 100% acetonitrile in water. Product containing fractions were concentrated under reduced pressure to give an off-white solid (100 mg, 77% yield). LCMS m / z = 813.2 (M+H).

[0258] Step 2. (R)-4-Amino-1-(4-((6-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)- 1H-indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)sulfonyl)piperidin-1-yl)butan- 1-one bis(trifluoroacetic acid) salt. tert-Butyl (R)-(4-(4-((6-(5-(5-(1-(3,5-dichloropyridin-4- yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)sulfonyl)piperidin- 1-yl)-4-oxobutyl)carbamate (150 mg, 0.19 mmol, 1 equiv) in dichloromethane (2 mL) was treated with trifluoroacetic acid (2 mL) at room temperature for 3 hours. The mixture was - 113 - 4896-4398-0599.1120039.000146 | TYRA.037PCT concentrated under reduced pressure to give a dark red oil (174 mg, 99% yield). LCMS m / z = 713.2 (M+H, free base).

[0259] Step 3.5-[[4-[4-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H- indazol-3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]-heptan-2-yl]sulfonyl]-1-piperidyl]-4-oxo- butyl]amino]-2-(2,6-dioxo-3-piperidyl)-isoindoline-1,3-dione. N,N-Diisopropylethylamine (1.0 mL, 5.54 mmol, 30 equiv) was added to a mixture of (R)-4-amino-1-(4-((6-(5-(5-(1-(3,5- dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2- yl)sulfonyl)piperidin-1-yl)butan-1-one bis(trifluoroacetic acid) salt (174 mg, 0.19 mmol, 1.0 equiv) and 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (200 mg, 0.63 mmol, 3.3 equiv) in dimethyl sulfoxide (3 mL) at room temperature. The mixture was heated at 80 °C for 16 hours. After cooling to room temperature, the mixture was concentrated to remove most N,N-diisopropylethylamine. The residue was purified on a Biotage automated chromatography system (RediSep Rf GOLD 100 g HP C18 column), eluting with a gradient of 0 to 100% acetonitrile (w / 0.1% vol / vol acetic acid) in water (w / 0.1% vol / vol acetic acid). The product containing fractions were combined (~25 mL), adjusted to pH >8 with 28% ammonium hydroxide (0.06 mL) and lyophilized to give an off-white solid (5 mg, 3% yield). LCMS m / z = 969.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ = 13.00 (br s, 1H), 11.03 (br s, 1H), 8.59 (s, 2H), 8.51 (d, J = 2.0 Hz, 1H), 7.87 (dd, J = 2.2, 8.7 Hz, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.16 (s, 2H), 7.09 (dd, J = 2.1, 9.0 Hz, 1H), 6.97 (d, J = 1.7 Hz, 1H), 6.86 (dd, J = 1.9, 8.5 Hz, 1H), 6.54 (d, J = 8.6 Hz, 1H), 6.11 (q, J = 6.5 Hz, 1H), 5.02 (dd, J = 5.3, 12.9 Hz, 1H), 4.52 (br d, J = 12.3 Hz, 1H), 4.17 (s, 6H), 4.11 (s, 6H), 3.98 (br d, J = 11.4 Hz, 1H), 3.23-3.17 (m, 2H), 3.06 (br t, J = 12.0 Hz, 1H), 2.92-2.82 (m, 1H), 2.59-2.53 (m, 2H), 2.46 (br d, J = 6.8 Hz, 1H), 2.00 (br d, J = 10.4 Hz, 4H), 1.81 (br d, J = 7.1 Hz, 1H), 1.76 (d, J = 6.6 Hz, 4H), 1.54 (br d, J = 9.5 Hz, 2H), 1.40 (br d, J = 9.0 Hz, 2H). Example 19.4-[4-[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3- yl]-2-pyridyl]-2,6-diazaspiro[3.3]-heptane-2-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4- hydroxy-1-piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione. - 114 -4896-4398-0599.1120039.000146 | TYRA.037PCT Step 3Step 1 Step 2Example 19

[0260] Step 1. tert-Butyl 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)-4-hydroxypiperidin-4-yl)acetate. A mixture of (2,6-dioxo-3-piperidyl)-4-fluoro- isoindoline-1,3-dione (430 mg, 1.56 mmol, 1 equiv), tert-butyl 2-(4-hydroxy-4- piperidyl)acetate (503 mg, 2.34 mmol, 1.5 equiv), and N,N-diisopropylethylamine (2.7 mL, 15.6 mmol, 10 equiv) in dimethylsulfoxide (5 mL) was stirred at 80 °C for 18 hours. The mixture was cooled to room temperature, poured into water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated brine (2 x 15 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (Biotage Sfar KP- Amino 220 g column), eluting with a gradient of 0 to 100% ethyl acetate in hexanes to give a yellow solid (470 mg, 62% yield). LCMS m / z = 472.2 (M+H).

[0261] Step 2.2-(1-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-4- hydroxypiperidin-4-yl)acetic acid.4M HCl in 1,4-dioxane (3.0 mL, 9.54 mmol, 30 equiv) was added to a suspension of tert-butyl 2-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin- 4-yl]-4-hydroxy-4-piperidyl]acetate (150 mg, 0.32 mmol, 1 equiv) in 1,4-dioxane (0.75 mL) and the mixture was stirred at room temperature for 23 hours. The volatiles were evaporated under reduced pressure and the residue was dried under vacuum at 40 °C for 5 hours to give a yellow solid (164 mg), which was used directly in the next step. LCMS m / z = 416.1 (M+H).

[0262] Step 3.4-[4-[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H- indazol-3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]-heptane-2-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4- - 115 - 4896-4398-0599.1120039.000146 | TYRA.037PCT hydroxy-1-piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione. A mixture of [6-[5-[5- [(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6- diazaspiro[3.3]heptan-2-yl]-(4-piperidyl)methanone (70 mg, 118 µmol, 1 equiv) and 2-(1-(2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-4-hydroxypiperidin-4-yl)acetic acid (65 mg, 125 µmol, 1.06 equiv) in N,N-dimethylformamide (1 mL) was sequentially treated with N,N-diisopropylethylamine (70 µL, 0.4 mmol, 3.4 equiv) and propylphosphonic anhydride (50% w / w solution in ethyl acetate, 150 µL, 256 µmol, 2.2 equiv). The reaction was stirred at room temperature for 5 hours. The reaction was purified directly on a Biotage automated chromatography system (RediSep Gold C1830 g column), eluting with a gradient of 0 to 40% acetonitrile in water to give a yellow solid (66 mg, 56% yield). LCMS m / z = 989.3 (M+H); δ 1H NMR (400 MHz, DMSO-d6) δ = 12.99 (s, 1H), 11.06 (s, 1H), 8.59 (s, 2H), 8.52 (d, J = 2.0 Hz, 1H), 7.87 (dd, J = 2.0, 8.6 Hz, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.46 (d, J = 9.0 Hz, 1H), 7.36 (d, J = 8.6 Hz, 1H), 7.31 (d, J = 7.1 Hz, 1H), 7.17 (s, 1H), 7.09 (dd, J = 2.2, 9.0 Hz, 1H), 6.55 (d, J = 8.7 Hz, 1H), 6.11 (q, J = 6.7 Hz, 1H), 5.12-5.05 (m, 2H), 4.42 (s, 3H), 4.17 (s, 4H), 4.12-4.02 (m, 3H), 3.45 (br d, J = 6.5 Hz, 2H), 3.28-3.19 (m, 3H), 3.08 (br t, J = 11.9 Hz, 1H), 2.93-2.81 (m, 1H), 2.71-2.63 (m, 1H), 2.63-2.53 (m, 4H), 2.06-1.99 (m, 1H), 1.86-1.78 (m, 2H), 1.76 (d, J = 6.7 Hz, 3H), 1.69 (br d, J = 13.6 Hz, 4H), 1.57-1.44 (m, 1H), 1.41-1.28 (m, 1H). Example 20.5-[[2-[4-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]- 2-pyridyl]-2,6-diazaspiro[3.3]-heptan-2-yl]sulfonyl]-1-piperidyl]-2-oxo-ethyl]amino]-2- (2,6-dioxo-3-piperidyl)isoindoline-1,3-dione. - 116 -4896-4398-0599.1120039.000146 | TYRA.037PCT ep 2 Step 3Example 20Step 1

[0263] Step 1. tert-Butyl (R)-(2-(4-((6-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)- 1H-indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)sulfonyl)piperidin-1-yl)-2- oxoethyl)carbamate. Triethylamine (0.14 mL, 0.95 mmol, 4.0 equiv) and 50 wt% propylphosphonic anhydride in ethyl acetate solution (0.28 mL, 0.48 mmol, 2.0 equiv) were sequentially added to a solution of 5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-[2-(4- piperidylsulfonyl)-2,6-diazaspiro[3.3]heptan-6-yl]-3-pyridyl]-1H-indazole (150 mg, 0.24 mmol, 1.0 equiv) and 2-(tert-butoxycarbonylamino)acetic acid (42 mg, 0.24 mmol, 1.0 equiv) in N,N-dimethylformamide (10 mL) at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was purified on a Biotage automated chromatography system (RediSep Rf GOLD 100 g HP C18 column), eluting with a gradient of 0 to 100% acetonitrile in water. Product containing fractions were concentrated under reduced pressure to give an off-white solid (187 mg, 99% yield). LCMS m / z = 785.2 (M+H).

[0264] Step 2. (R)-2-Amino-1-(4-((6-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)- 1H-indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)sulfonyl)piperidin-1-yl)ethan- 1-one bis(trifluoroacetic acid) salt. tert-Butyl (R)-(2-(4-((6-(5-(5-(1-(3,5-dichloropyridin-4- yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)sulfonyl)piperidin- 1-yl)-2-oxoethyl)carbamate (187 mg, 0.24 mmol, 1 equiv) in dichloromethane (2 mL) was treated with trifluoroacetic acid (2 mL) at room temperature for 3 hours. The mixture was - 117 - 4896-4398-0599.1120039.000146 | TYRA.037PCT concentrated under reduced pressure to give a dark red oil (217 mg, 99%). LCMS m / z = 685.1 (M+H, free base).

[0265] Step 3.5-((2-(4-((6-(5-(5-((R)-1-(3,5-Dichloropyridin-4-yl)ethoxy)-1H- indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)sulfonyl)piperidin-1-yl)-2- oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. N,N- Diisopropylethylamine (1.3 mL, 7.13 mmol, 30 equiv) was added to a mixture of (R)-2- amino-1-(4-((6-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)-2,6- diazaspiro[3.3]heptan-2-yl)sulfonyl)piperidin-1-yl)ethan-1-one bis(trifluoroacetic acid) salt (217 mg, 0.24 mmol, 1.0 equiv) and 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (197 mg, 0.71 mmol, 3.0 equiv) in dimethyl sulfoxide (3 mL) at room temperature. The mixture was heated at 80 °C for 16 hours. After cooling to room temperature, the mixture was concentrated to remove most N,N-diisopropylethylamine. The residue was purified on a Biotage automated chromatography system (RediSep Rf GOLD 100 g HP C18 column), eluting with a gradient of 0 to 100% acetonitrile (w / 0.1% vol / vol acetic acid) in water (w / 0.1% vol / vol acetic acid). The product containing fractions were combined (~50 mL), then adjusted to pH 8 with 28% ammonium hydroxide (0.12 mL) and lyophilized to give an off- white solid (16 mg, 7% yield). LCMS m / z = 941.2 (M+H); δ 1H NMR (400 MHz, DMSO- d6) δ = 13.00 (br s, 1H), 11.05 (br s, 1H), 8.59 (s, 2H), 8.51 (d, J = 2.0 Hz, 1H), 7.87 (dd, J = 2.1, 8.6 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.20-6.98 (m, 4H), 6.54 (d, J = 8.6 Hz, 1H), 6.11 (q, J = 6.6 Hz, 1H), 5.04 (dd, J = 5.4, 12.8 Hz, 1H), 4.50 (br d, J = 12.1 Hz, 1H), 4.21-4.09 (m, 10H), 3.50-3.39 (m, 2H), 3.12 (br t, J = 11.7 Hz, 1H), 2.93-2.82 (m, 1H), 2.76-2.64 (m, 1H), 2.63-2.53 (m, 2H), 2.09-1.96 (m, 3H), 1.76 (d, J = 6.6 Hz, 3H), 1.71-1.63 (m, 1H), 1.50-1.34 (m, 2H). Example 21.5-[4-[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3- yl]-2-pyridyl]-2,6-diazaspiro[3.3]-heptane-2-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4- hydroxy-1-piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione.- 118 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0266] Step 1. tert-butyl 2-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5- yl]-4-hydroxy-4-piperidyl]acetate)acetate. A mixture of 2-(2,6-dioxo-3-piperidyl)-5-fluoro- isoindoline-1,3-dione (430 mg, 1.56 mmol, 1 equiv), tert-butyl 2-(4-hydroxy-4- piperidyl)acetate (0.5 g, 2.33 mmol, 1.5 equiv) and N,N-diisopropylethylamine (2.7 mL, 15.6 mmol, 10 equiv) in dimethylsulfoxide (5 mL) was stirred at 80 °C for 18 hours. The mixture was cooled to room temperature, poured into water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated brine (2 x 15 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (Biotage Sfar KP-Amino 220 g column), eluting with a gradient of 0 to 100% ethyl acetate in hexanes to give a yellow solid (510 mg, 67% yield). LCMS m / z = 472.2 (M+H).

[0267] Step 2.2-(1-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-4- hydroxypiperidin-4-yl)acetic acid.4M HCl in 1,4-dioxane (2.4 mL, 9.5 mmol, 30 equiv) was added to a suspension of tert-butyl 2-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5- yl]-4-hydroxy-4-piperidyl]acetate (150 mg, 0.32 mmol, 1 equiv) in 1,4-dioxane (0.75 mL), and the resulting mixture was stirred at room temperature for 23 hours. The volatiles were removed under reduced pressure and the residue was dried under vacuum at 40 °C for 5 hours to give a yellow solid (157 mg), which was used directly in the next step. LCMS m / z = 416.1 (M+H).

[0268] Step 3.5-(4-(2-(4-(6-(5-(5-((R)-1-(3,5-Dichloropyridin-4-yl)ethoxy)-1H- indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)piperidin-1-yl)-2- oxoethyl)-4-hydroxypiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. A mixture of [6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6- diazaspiro[3.3]heptan-2-yl]-(4-piperidyl)methanone (50 mg, 84 µmol, 1 equiv) and 2-(1-(2- (2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-4-hydroxypiperidin-4-yl)acetic acid (50 mg, 96 µmol, 1.1 equiv) in N,N-dimethylformamide (0.75 mL) was sequentially treated with N,N-diisopropylethylamine (50 µL, 0.27 mmol, 3.4 equiv) and propylphosphonic anhydride (50% w / w solution in ethyl acetate, 40 µL, 0.14 mmol, 1.6 equiv). The reaction was stirred at room temperature for 4 hours. The reaction mixture was purified directly on a Biotage automated chromatography system (RediSep Gold C1830 g column), eluting with a gradient of 0 to 50% acetonitrile in water to give a yellow solid (25 mg, 38% yield over 2 steps). LCMS m / z = 989.3 (M+H); δ 1H NMR (400 MHz, DMSO-d6) δ = 12.99 (s, 1H), 11.06 (s, - 119 -4896-4398-0599.1120039.000146 | TYRA.037PCT 1H), 8.59 (s, 2H), 8.52 (d, J = 2.1 Hz, 1H), 7.87 (dd, J = 2.1, 8.6 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.45 (d, J = 8.9 Hz, 1H), 7.32 (s, 1H), 7.25 (br d, J = 8.7 Hz, 1H), 7.16 (s, 1H), 7.09 (dd, J = 2.0, 9.0 Hz, 1H), 6.54 (d, J = 8.7 Hz, 1H), 6.11 (q, J = 6.7 Hz, 1H), 5.75 (s, 2H), 5.13 (s, 1H), 5.06 (dd, J = 5.4, 12.9 Hz, 1H), 4.42 (s, 3H), 4.17 (s, 4H), 4.07 (s, 2H), 4.01 (br d, J = 12.5 Hz, 1H), 3.79 (br d, J = 11.9 Hz, 2H), 3.42-3.34 (m, 2H), 3.05 (br t, J = 11.8 Hz, 1H), 2.93-2.83 (m, 1H), 2.69-2.52 (m, 4H), 2.04-1.97 (m, 1H), 1.76 (d, J = 6.6 Hz, 3H), 1.65 (br s, 6H), 1.55-1.42 (m, 1H), 1.38-1.28 (m, 1H). Example 22.2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]ethyl 4-[6-[5-[5-[(1R)- 1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]- heptane-2-carbonyl]piperidine-1-carboxylate.Example 22

[0269] A solution of 1,1′-carbonyldiimidazole (28 mg, 0.17 mmol, 2 equiv) in THF (0.25 mL) was added at 0 °C under a nitrogen atmosphere to a solution of 2-(2,6-dioxo- 3-piperidyl)-4-(2-hydroxyethyl)isoindoline-1,3-dione (35 mg, 0.12 mmol, 1.4 equiv) in THF (0.2 mL). After 10 minutes the ice bath was removed, and the reaction mixture was stirred at room temperature for 3 hours. LCMS analysis showed formation of 2-[2-(2,6-dioxo-3- piperidyl)-1,3-dioxo-isoindolin-4-yl]ethyl imidazole-1-carboxylate (LCMS m / z = 397.1 (M+H)). The reaction mixture was added to a stirred solution of [6-[5-[5-[(1R)-1-(3,5- dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]heptan-2-yl]-(4- piperidyl)methanone (50 mg, 0.84 mmol, 1 equiv) in N,N-dimethylformamide (0.5 mL) at room temperature. The reaction was stirred at room temperature for 68 hours. The mixture was purified directly on a Biotage automated chromatography system (RediSep Gold C1830 g column), eluting with a gradient of 0 to 100 acetonitrile in water to give a light yellow solid (13 mg, 16% yield). LCMS m / z = 920.2 (M+H); δ 1H NMR (400 MHz, DMSO-d6) δ = 12.99 (s, 1H), 11.11 (s, 1H), 8.59 (s, 2H), 8.52 (s, 1H), 7.87 (br d, J = 8.6 Hz, 1H), 7.83-7.78 (m, 2H), 7.77-7.72 (m, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.17 (s, 1H), 7.09 (br d, J = 8.9 Hz, 1H), - 120 -4896-4398-0599.1120039.000146 | TYRA.037PCT 6.54 (d, J = 8.8 Hz, 1H), 6.11 (q, J = 6.7 Hz, 1H), 5.14 (dd, J = 5.4, 13.0 Hz, 1H), 4.38 (s, 2H), 4.34-4.22 (m, 2H), 4.16 (s, 4H), 4.06 (s, 2H), 3.88 (br s, 1H), 3.81 (br s, 1H), 3.42-3.34 (m, 2H), 2.96-2.85 (m, 1H), 2.76 (br t, J = 12.4 Hz, 2H), 2.64-2.53 (m, 2H), 2.38 (br t, J = 10.9 Hz, 1H), 2.07 (s, 3H), 1.76 (d, J = 6.6 Hz, 3H), 1.57 (br s, 2H), 1.35-1.22 (m, 2H). Example 23.3-[4-[4-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]- 2-pyridyl]-2,6-diazaspiro[3.3]-heptan-2-yl]sulfonyl]-1-piperidyl]-3-methyl-2-oxo- benzimidazol-1-yl]piperidine-2,6-dione.Example 23

[0270] Step 1.4-Bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,3- dihydro-2H-benzo[d]imidazol-2-one. A 60% dispersion of sodium hydride in mineral oil(1.32 g, 33.0 mmol, 1.5 equiv) was added to a solution of 4-bromo-3-methyl-1H- benzimidazol-2-one (5.0 g, 22.0 mmol, 1.0 equiv) in N,N-dimethylacetamide (70 mL) and tetrahydrofuran (25 mL) at 0 °C. After 15 minutes, (2-(chloromethoxy)ethyl)trimethylsilane (4.8 mL, 26.4 mmol, 1,2 equiv) was added dropwise. The mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction was diluted with water (200 mL), extracted with dichloromethane (2 x 150 mL). The combined organic layers were washed with water (150 mL), dried over sodium sulfate, filtered, and concentrated under reduced - 121 -4896-4398-0599.1120039.000146 | TYRA.037PCT pressure. The residue was purified on a Biotage automated chromatography system (Yamazen 200 g + 135 g, stacked), eluting with a gradient of 0 to 30% ethyl acetate in hexanes to give an amber oil (7.0 g, 89% yield). LCMS m / z = 379.0 (M+Na).

[0271] Step 2. tert-Butyl 1-(3-methyl-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)- 2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-4-carboxylate. Tris(dibenzylideneacetone)dipalladium(0) (256 mg, 0.28 mmol, 0.1 equiv), RuPhos (261 mg, 0.56 mmol, 0.2 equiv) and sodium tert-butoxide (672 mg, 7.0 mmol, 2.5 equiv) were added sequentially to a solution of tert-butyl piperidine-4-carboxylate (570 mg, 3.1 mmol, 1.1 equiv) and 4-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H- benzo[d]imidazol-2-one (1.0 g, 2.8 mmol, 1.0 equiv) at room temperature in toluene (20 mL). The mixture was sparged with nitrogen for 10 minutes and then heated at 80 °C for 12 hours. After cooling to room temperature, the reaction was diluted with water (20 mL) and extracted with ethyl acetate (200 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (Yamazen 55 g silica gel column), eluting with a gradient of 0 to 50% ethyl acetate in hexanes to give a yellow solid (1.02 g, 79% yield). LCMS m / z = 462.2 (M+H).

[0272] Step 3. tert-Butyl 1-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4- yl)piperidine-4-carboxylate.1M Tetrabutylammonium fluoride solution in tetrahydrofuran (11 mL, 11 mmol, 5.0 equiv) was added to tert-butyl 1-(3-methyl-2-oxo-1-((2- (trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-4- carboxylate (1.02 g, 2.2 mmol, 1.0 equiv). The mixture was heated at 75 °C for 16 hours. After cooling to room temperature, the mixture was divided into two equal portions, and each purified on a Biotage automated chromatography system (RediSep Rf GOLD 100 g HP C18 column), eluting with a gradient of 0 to 100% acetonitrile in water and combined to give off- white solid (450 mg, 61% yield). LCMS m / z = 332.2 (M+H).

[0273] Step 4. tert-Butyl 1-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-4-carboxylate. Potassium tert-butoxide (457 mg, 4.1 mmol, 3.0 equiv) was added to a solution of tert-butyl 1-(3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-4-carboxylate (450 mg, 1.36 mmol, 1.0 equiv) in tetrahydrofuran (60 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hour and then heated to 45 °C. A solution of 3-bromo-1-[(4-methoxyphenyl)methyl]- - 122 -4896-4398-0599.1120039.000146 | TYRA.037PCT piperidine-2,6-dione (1.27 g, 4.1 mmol, 3.0 equiv) in tetrahydrofuran (20 mL) was added dropwise. After heating at 45 °C for 6 additional hours, the mixture was cooled to 0 °C, diluted with water (40 mL) and extracted with dichloromethane (2 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure The residue was purified on a Biotage automated chromatography system (Yamazen 55 g silica gel column), eluting with a gradient of 0 to 100% ethyl acetate in hexanes to give an off-white solid (179 mg, 23% yield). LCMS m / z = 563.2 (M+H).

[0274] Step 5.1-(1-(2,6-Dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)piperidine-4-carboxylic acid. Trifluoromethanesulfonic acid (1.1 mL, 11.9 mmol, 37.4 equiv) was added to a solution of tert-butyl 1-(1-(1-(4-methoxybenzyl)-2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-4- carboxylate (179 mg, 0.32 mmol, 1.0 equiv) in trifluoroacetic acid (2.5 mL) at room temperature. The mixture was heated at 65 °C for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue was purified on a Biotage automated chromatography system (RediSep Rf GOLD 100 g HP C18 column), eluting with a gradient of 0 to 100% acetonitrile in water. The product containing fractions were combined and lyophilized to give an off-white solid (62 mg, 50% yield). LCMS m / z = 387.2 (M+H).

[0275] Step 6.3-(4-(4-(6-(5-(5-((R)-1-(3,5-Dichloropyridin-4-yl)ethoxy)-1H- indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)piperidin-1-yl)-3-methyl-2- oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione. Triethylamine (0.12 mL, 0.83 mmol, 8.0 equiv) and 50 wt% propylphosphonic anhydride in ethyl acetate solution (0.25 mL, 0.41 mmol, 4.0 equiv) were sequentially added to a solution of 1-(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-4- carboxylic acid (40 mg, 0.1 mmol, 1.0 equiv) and 3-[6-(2,6-diazaspiro[3.3]heptan-2-yl)-3- pyridyl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazole (50 mg, 0.1 mmol, 1.0 equiv) in N,N-dimethylformamide (8 mL) at room temperature. The mixture was stirred at room temperature for 16 hours. The reaction mixture was purified on a Biotage automated chromatography system (RediSep Rf GOLD 100 g HP C18 column) eluting with a gradient of 0 to 100% acetonitrile (w / 0.1% vol / vol acetic acid) in water (w / 0.1% vol / vol acetic acid). The product containing fractions were combined (~100 mL), basified with 28% ammonium hydroxide solution (0.25 mL) to pH 8 and lyophilized to give an off-white solid (39 mg, 44% - 123 -4896-4398-0599.1120039.000146 | TYRA.037PCT yield). LCMS m / z = 849.3 (M+H); 1H NMR (400 MHz, DMSO-d6) δ = 13.00 (br s, 1H), 11.07 (br s, 1H), 8.59 (s, 2H), 8.52 (d, J = 2.0 Hz, 1H), 7.87 (dd, J = 2.0, 8.6 Hz, 1H), 7.46 (d, J = 9.0 Hz, 1H), 7.17 (s, 1H), 7.09 (dd, J = 2.0, 9.0 Hz, 1H), 7.02-6.94 (m, 1H), 6.94-6.85 (m, 2H), 6.55 (d, J = 8.7 Hz, 1H), 6.11 (q, J = 6.6 Hz, 1H), 5.35 (br dd, J = 5.4, 12.8 Hz, 1H), 4.45 (s, 2H), 4.18 (s, 4H), 4.10 (s, 2H), 3.64 (s, 3H), 3.14 (br d, J = 11.4 Hz, 2H), 2.95-2.83 (m, 1H), 2.79-2.58 (m, 4H), 2.35 (br d, J = 14.4 Hz, 1H), 2.05-1.95 (m, 1H), 1.76 (br d, J = 6.6 Hz, 7H). Example 24.5-[[4-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]- 2-pyridyl]-2,6-diazaspiro[3.3]-heptane-2-carbonyl]-1-piperidyl]-4-oxo-butyl]amino]-2- (2,6-dioxo-3-piperidyl)isoindoline-1,3-dione.

[0276] Step 1. tert-Butyl (R)-(4-(4-(6-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)- 1H-indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)piperidin-1-yl)-4- oxobutyl)carbamate. A mixture of [6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H- indazol-3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]heptan-2-yl]-(4-piperidyl)methanone (477 mg, 1 equiv, 0.68 mmol) and 4-(tert-butoxycarbonylamino)butanoic acid (167 mg, 1.2 equiv, 0.82 mmol) in THF (18 mL) was sequentially treated with N,N-diisopropylethylamine (0.4 mL, 3.4 equiv, 2.3 mmol) and propylphosphonic anhydride (50% w / w solution in ethyl acetate, 325 µL, 1.6 equiv, 1.1 mmol). The reaction was stirred at room temperature for 4 hours, then concentrated under reduced pressure. The residue was diluted with water (15 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a light-yellow foam (360 mg), which was used in the next step. LCMS m / z = 777.3 (M+H).

[0277] Step 2. (R)-4-Amino-1-(4-(6-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)- 1H-indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)piperidin-1-yl)butan-1- - 124 -4896-4398-0599.1120039.000146 | TYRA.037PCT one. Trifluoroacetic acid (3.6 mL) was added to a solution of tert-butyl (R)-(4-(4-(6-(5-(5-(1- (3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane- 2-carbonyl)piperidin-1-yl)-4-oxobutyl)carbamate (0.36 g, 0.44 mmol, 1 equiv) in dichloromethane (3.6 mL) at room temperature. After stirring at room temperature for 3.5 hours, the volatiles were evaporated under reduced pressure. Toluene (5 mL) was added to the residue and the resulting mixture was evaporated to dryness under reduced pressure. The residue was dissolved in saturated sodium carbonate (20 mL) and extracted with 10% methanol in ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated in isopropanol (50 mL) at room temperature for 30 minutes. The solid was filtered off and the filtrate was concentrated under reduced pressure. The product was dried under vacuum at 40 °C for 1 hour to give a tan foam (0.72 g, >100% yield), which was used directly in the next step. LCMS m / z = 677.2 (M+H).

[0278] Step 3.5-((4-(4-(6-(5-(5-((R)-1-(3,5-Dichloropyridin-4-yl)ethoxy)-1H- indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)piperidin-1-yl)-4- oxobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. A mixture of (R)-4- amino-1-(4-(6-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)-2,6- diazaspiro[3.3]heptane-2-carbonyl)piperidin-1-yl)butan-1-one (130 mg, 1 equiv, 0.19 mmol 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (63 mg, 1.2 equiv, 0.23 mmol) and triethylamine (90 µL, 3.4 equiv, 0.64 mmol) in dimethylsulfoxide (3 mL) was heated at 80 °C for 18 hours. The reaction was cooled to room temperature, diluted with water (15 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with saturated brine (2 x 15 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (RediSep Gold C1830 g column), eluting with a gradient of 0 to 100% acetonitrile in water to give a yellow solid (10 mg, 13% yield over 2 steps). LCMS m / z = 933.3 (M+H); 1H NMR (400 MHz, CDCl3) δ = 9.97 (br s, 1H), 8.67 (s, 1H), 8.43 (s, 2H), 8.20-8.11 (m, 1H), 7.93 (dd, J = 1.8, 8.7 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.40-7.36 (m, 1H), 7.23-7.19 (m, 1H), 7.15 (dd, J = 1.9, 9.1 Hz, 1H), 6.96 (s, 1H), 6.75 (d, J = 8.6 Hz, 1H), 6.44 (d, J = 8.6 Hz, 1H), 6.06 (q, J = 6.7 Hz, 1H), 5.50 (br s, 1H), 4.93 (dd, J = 5.3, 12.2 Hz, 1H), 4.59 (br d, J = 13.1 Hz, 1H), 4.41 (s, 2H), 4.30-4.22 (m, 6H), 3.91 (br d, J = 13.2 Hz, 1H), 3.33-3.24 (m, 2H), 3.10 (br t, J = 9.4 Hz, 1H), 2.92-2.72 (m, 4H), 2.53-2.47 (m, 2H), 2.45 (br d, J = 5.0 Hz, 1H), 2.13 (br - 125 -4896-4398-0599.1120039.000146 | TYRA.037PCT dd, J = 5.3, 13.4 Hz, 1H), 2.06 (br dd, J = 7.5, 13.7 Hz, 2H), 1.83 (d, J = 6.7 Hz, 3H), 1.80- 1.68 (m, 4H). Example 25.3-[4-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]-heptane-2-carbonyl]-1-piperidyl]-3-methyl-2-oxo- benzimidazol-1-yl]piperidine-2,6-dione.

[0279] Triethylamine (0.11 mL, 0.77 mmol, 8.0 equiv) and 50 wt% propylphosphonic anhydride in ethyl acetate solution (0.23 mL, 0.38 mmol, 4.0 equiv) were sequentially added to a solution of 1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-4-yl]piperidine-4-carboxylic acid (37 mg, 0.096 mmol, 1.0 equiv) and 5-[(1R)- 1-(3,5-dichloro-4-pyridyl)ethoxy]-3-[6-[2-(4-piperidylsulfonyl)-2,6-diazaspiro[3.3]heptan-6- yl]-3-pyridyl]-1H-indazole (60 mg, 0.096 mmol, 1.0 equiv) in N,N-dimethylformamide (5 mL) at room temperature. The mixture was stirred at room temperature for 16 hours. The reaction mixture was purified on a Biotage automated chromatography system (RediSep Rf GOLD 100 g HP C18 column), eluting with a gradient of 0 to 100% acetonitrile (w / 0.1% vol / vol acetic acid) in water (w / 0.1% vol / vol acetic acid). The product containing fractions were combined (100 mL), basified with 28% ammonium hydroxide solution (0.25 mL) to pH 8 and lyophilized to give an off-white solid (51 mg, 53% yield). LCMS m / z = 996.3 (M+H); 1H NMR (400 MHz, DMSO-d6) δ = 12.99 (s, 1H), 11.07 (br s, 1H), 8.59 (s, 2H), 8.51 (s, 1H), 7.87 (dd, J = 2.0, 8.6 Hz, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.16 (s, 1H), 7.09 (dd, J = 2.0, 8.9 Hz, 1H), 6.99 (t, J = 8.0 Hz, 1H), 6.88 (t, J = 8.0 Hz, 2H), 6.54 (d, J = 8.7 Hz, 1H), 6.11 (q, J = 6.5 Hz, 1H), 5.35 (br dd, J = 5.3, 12.5 Hz, 1H), 4.54 (br d, J = 11.9 Hz, 1H), 4.18 (s, 4H), 4.13 (s, 5H), 3.64 (s, 3H), 3.48-3.40 (m, 1H), 3.19-3.08 (m, 3H), 2.90-2.73 (m, 4H), 2.72-2.58 (m, 3H), 2.11-1.96 (m, 3H), 1.88-1.69 (m, 7H), 1.55 (br d, J = 8.6 Hz, 1H), 1.41 (br d, J = 11.6 Hz, 1H). Example 26.3-[6-[1-[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3- yl]-2-pyridyl]-2,6-diazaspiro[3.3]-heptane-2-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4- piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione. - 126 -4896-4398-0599.1120039.000146 | TYRA.037PCT tep 3 Step 4Step 5 Step 4Step 5 Step 1Step 27Step 8 Step 1Step 2Step 8 Step 6 StExample 26 Step 6Example 26

[0280] Step 1.6-Bromo-3-iodo-1-methyl-1H-indazole. Potassium hydroxide (2.20 g, 39.2 mmol, 2.5 equiv) and iodomethane (1.50 mL, 24 mmol, 1.5 equiv) were sequentially added to a solution of 6-bromo-3-iodo-1H-indazole (5.00 g, 15.4 mmol) in acetone (30 mL) at room temperature After stirring for 3 hours, the mixture was diluted dropwise with water (90 mL). The resulting solid was filtered and washed with water (60 mL). The solids were dissolved in dichloromethane then purified on a Biotage automated chromatography system (Yamazen 120 g, 40µ silica gel column), eluting with a gradient of 0 to 10% ethyl acetate in hexanes to give a white solid (3.35 g, 64% yield). LCMS m / z = 337 (M+H).

[0281] Step 2. Bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole.6-Bromo- 3-iodo-1-methyl-1H-indazole (2.0 g, 5.9 mmol, 1 equiv), 2,6-dibenzyloxy-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.48 g, 5.9 mmol, 1 equiv), cesium carbonate (3.48 g, 10.6 mmol, 1.8 equiv) and [1,1′-bis(diphenylphosphino)- - 127 - 4896-4398-0599.1120039.000146 | TYRA.037PCT ferrocene]dichloropalladium(II) dichloromethane complex (0.24 g, 0.3 mmol, 0.05 equiv) in a mixture of THF (60 mL) and water (10 mL) was sparged with nitrogen for 10 minutes then heated at 60 °C for 96 hours under nitrogen. The mixture was cooled to room temperature then extracted with ethyl acetate (100 mL and 50 mL). The combined organic layers were concentrated under reduced pressure onto silica gel (30 g). The residue was purified on a Biotage automated chromatography system (Yamazen 55 g, 40µ silica gel column), eluting with a gradient of 0 to 10% ethyl acetate in hexanes to give an amber oil that solidified to an orange solid (2.2 g, 74% yield). LCMS m / z = 500 (M+H).

[0282] Step 3. tert-Butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H- indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate. Bromo-3-(2,6-dibenzyloxy-3-pyridyl)- 1-methyl-indazole (1.25 g, 2.5 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.16 g, 3.7 mmol, 1.5 equiv), tripotassium phosphate monohydrate (0.60 g, 2.6 mmol, 1.0 equiv) and [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) dichloromethane complex (0.21 g, 0.25 mmol, 0.10 equiv) in a mixture of 1,4-dioxane (30 mL) and water (5 mL) was sparged with nitrogen for 10 minutes then heated at 80 °C for 45 hours under nitrogen. The mixture was cooled to room temperature, diluted with water (10 mL) then extracted with ethyl acetate (2 x 60 mL). The combined organic layers were concentrated under reduced pressure onto silica gel (30 g). The residue was purified on a Biotage automated chromatography system (Yamazen 55 g, 40µ silica gel column), eluting with a gradient of 0 to 40% ethyl acetate in hexanes to give an amber oil (1.05 g, 69% yield). LCMS m / z = 603 (M+H).

[0283] Step 4. tert-Butyl 4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6- yl]piperidine-1-carboxylate. tert-Butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6- yl]-3,6-dihydro-2H-pyridine-1-carboxylate (1.05 g, 1.7 mmol) and 10% palladium on carbon (50% wet, 0.56 g, 0.26 mmol, 0.15 equiv) in a mixture of ethanol (20 mL) and ethyl acetate (20 mL) was hydrogenated at 50 psi for 70 hours. The mixture was filtered through a pad of Celite, which was washed with a 1 to 1 mixture of ethanol and ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure to give a green oil. The residue was purified on a Biotage automated chromatography system (Yamazen 40 g, 40µ silica gel column), eluting with a gradient of 0 to 90% ethyl acetate in hexanes to give a white solid (0.60 g, 80% yield). LCMS m / z = 427 (M+H). - 128 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0284] Step 5.3-[1-Methyl-6-(4-piperidyl)indazol-3-yl]piperidine-2,6-dione trifluoroacetic acid salt. tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6- yl]piperidine-1-carboxylate (0.60 g, 1.4 mmol) in dichloromethane (6 mL) was treated with trifluoroacetic acid (0.6 mL, 7.8 mmol, 5.5 equiv) at room temperature for 16 hours. The mixture was concentrated under reduced pressure, the residue was dissolved in dichloromethane (20 mL) and concentrated under reduced pressure. The residue was diluted with diethyl ether (20 mL) then concentrated under reduced pressure. The residue was dried under vacuum at 40 °C for 1 hour to give an amber oil (0.85 g, >100% yield), which was used in the next step. LCMS m / z = 327 (M+H, free base).

[0285] Step 6. tert-Butyl 2-[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-1- piperidyl]acetate.3-[1-Methyl-6-(4-piperidyl)indazol-3-yl]piperidine-2,6-dione TFA salt (0.85 g, ≤1.4 mmol) in N,N-dimethylformamide (6 mL) was sequentially treated with triethylamine (1.0 mL, 7.1 mmol, 5 equiv) and tert-butyl bromoacetate (0.25 mL, 1.7 mmol, 1.2 equiv) at room temperature. After 3 hours, the resulting slurry was diluted with water (12 mL) and the solids filtered off, washed with water (2 x 12 mL) and then dried under vacuum at 40 °C overnight to give a white solid (0.47 g, 76% yield over two steps). LCMS m / z = 441 (M+H).

[0286] Step 7.2-(4-(3-(2,6-Dioxopiperidin-3-yl)-1-methyl-1H-indazol-6- yl)piperidin-1-yl)acetic acid hydrochloride. tert-butyl 2-[4-[3-(2,6-dioxo-3-piperidyl)-1- methyl-indazol-6-yl]-1-piperidyl]acetate (0.45 g, 1.0 mmol) as a suspension in dichloromethane (5 mL) was treated with 4M HCl in dioxane (4 mL, 16 mmol, 16 equiv). After 20 minutes, the mixture was diluted with dichloromethane (10 mL). After 2 hours, the mixture was concentrated under reduced pressure. The residue was suspended in a 1 to 1 mixture of acetonitrile and THF (24 mL) and then treated with 4M HCl in dioxane (5 mL, 20 mmol, 20 equiv). The mixture was stirred at room temperature for 2 hours then heated at 50 °C overnight. The slurry was cooled to room temperature then concentrated under reduced pressure. The residue was suspended in THF (20 mL), concentrated under reduced pressure then dried under vacuum at 40 °C for 4 hours to give a beige solid (0.70 g, >100% yield), which was used directly in the next step. LCMS m / z = 385 (M+H, free base).

[0287] Step 8.3-[6-[1-[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H- indazol-3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]-heptane-2-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4- piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione. Propylphosphonic acid solution in - 129 -4896-4398-0599.1120039.000146 | TYRA.037PCT ethyl acetate (25% w / w, 0.25 mL, 0.42 mmol, 4.1 equiv) was added to a mixture of 2-(4-(3- (2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)acetic acid hydrochloride (48 mg, 0.11 mmol, 1.1 equiv), [6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol- 3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]heptan-2-yl]-(4-piperidyl)methanone (60 mg, 0.10 mmol, 1 equiv) and triethylamine (0.25 mL, 1.8 mmol, 18 equiv) in N,N-dimethylformamide (3 mL). After stirring at room temperature for 2 hours, the reaction mixture was directly purified on a Biotage automated chromatography system (Teledyne RediSep Gold 100 g, C18 column), eluting with a gradient of 0 to 80% acetonitrile in water to give a white solid after lyophilization (22 mg, 23% yield). LCMS m / z = 958 (M+H); δ 1H NMR (400 MHz, DMSO- d6) δ = 13.00 (br s, 1H), 10.86 (s, 1H), 8.59 (s, 2H), 8.52 (d, J = 2.0 Hz, 1H), 7.87 (dd, J = 2.0, 8.6 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 9.0 Hz, 1H), 7.43 (s, 1H), 7.17 (s, 1H), 7.09 (dd, J = 2.0, 8.9 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.55 (d, J = 8.7 Hz, 1H), 6.11 (q, J = 6.5 Hz, 1H), 4.43 (s, 2H), 4.33 (br dd, J = 5.1, 9.5 Hz, 2H), 4.17 (s, 5H), 4.08 (s, 2H), 3.98 (s, 3H), 3.25 (br s, 2H), 3.13-3.03 (m, 2H), 2.95 (br d, J = 9.8 Hz, 2H), 2.71-2.59 (m, 4H), 2.38- 2.29 (m, 1H), 2.17 (br dd, J = 5.4, 13.4 Hz, 3H), 1.87-1.64 (m, 10H), 1.62-1.52 (m, 1H), 1.33 (br d, J = 10.5 Hz, 1H). Example 27.3-[4-[1-[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3- yl]-2-pyridyl]-2,6-diazaspiro[3.3]-heptane-2-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4- piperidyl]-3-fluoro-anilino]piperidine-2,6-dione.

[0288] Step 1. tert-Butyl 4-(2-fluoro-4-nitrophenyl)-3,6-dihydropyridine-1(2H)- carboxylate.1-Bromo-2-fluoro-4-nitro-benzene (6.00 g, 27.3 mmol, 1.0 equiv) and tert-butyl - 130 -4896-4398-0599.1120039.000146 | TYRA.037PCT 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (8.43 g, 27.3 mmol, 1 equiv) in a mixture of 1,4-dioxane (60.0 mL) and water (15.0 mL) were sparged with nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (1.58 g, 1.36 mmol, 0.05 equiv) was added and the reaction sparged with nitrogen for 20 additional minutes. After heating at 90 °C for 18 hours the reaction was cooled to room temperature, and filtered through Celite (5 g), which was rinsed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and water (100 mL). The layers were separated, and the aqueous layer extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (Sorbtech 120 g silica gel column), eluting with a gradient of 0 to 10% ethyl acetate in hexanes to give a yellow solid (5.33 g, 61% yield).

[0289] Step 2. tert-Butyl 4-(4-amino-2-fluorophenyl)piperidine-1-carboxylate. tert- butyl 4-(2-fluoro-4-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylate (5.33 g, 16.5 mmol, 1.0 equiv) and 10% palladium on carbon (1.55 g, 1.46 mmol, 0.088 equiv) in methanol (150 mL) was hydrogenated at 50 psi for 24 hours. The reaction was filtered through Celite (10 g), which was rinsed with methanol (100 mL). The filtrate was concentrated under reduced pressure to give a tan solid (4.62 g, 95% yield).

[0290] Step 3. tert-Butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)piperidine-1-carboxylate. tert-Butyl 4-(4-amino-2-fluorophenyl)piperidine-1- carboxylate (4.62 g, 15.7 mmol, 1.0 equiv) was treated with 3-bromopiperidine-2,6-dione (7.53 g, 39.2 mmol, 2.5 equiv) and sodium bicarbonate (6.59 g, 78.5 mmol, 5.0 equiv) in N,N-dimethylformamide (90.0 mL) at 60 °C for 22 hours. After cooling to room temperature, the reaction was diluted with water (150 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (Sorbtech 120 g silica gel column), eluting with a gradient of 0 to 100% ethyl acetate in hexanes to give an off-white solid (2.49 g, 39% yield). LCMS m / z = 428 (M+Na).

[0291] Step 4.3-((3-Fluoro-4-(piperidin-4-yl)phenyl)amino)piperidine-2,6-dione. tert-Butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidine-1-carboxylate (2.49 g, 6.14 mmol, 1.0 equiv) was treated with 4M HCl in dioxane (20.0 mL, 80.0 mmol, 13.0 equiv) in dichloromethane (20 mL) at room temperature for 2.5 hours. The reaction was - 131 -4896-4398-0599.1120039.000146 | TYRA.037PCT concentrated under reduced pressure and redissolved in acetonitrile (50 mL). The pH was adjusted to 7 with saturated sodium bicarbonate. The mixture was filtered and concentrated under reduced pressure to give a green solid (1.82 g, 97% yield). LCMS m / z = 306 (M+H).

[0292] Step 5. tert-Butyl 2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)piperidin-1-yl)acetate.3-((3-Fluoro-4-(piperidin-4-yl)phenyl)amino)piperidine- 2,6-dione (300 mg, 0.983 mmol, 1.0 equiv) was treated with tert-butyl 2-bromoacetate (0.15 mL, 0.985 mmol, 1.0 equiv) and triethylamine (0.55 mL, 3.93 mmol, 4.0 equiv) in N,N- dimethylformamide (5.0 mL) at room temperature for 18 hours. The reaction was diluted with ethyl acetate (20 mL) and cold water (50 mL). The layers were separated, and the aqueous layer extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give an oil (347 mg, 84% yield). LCMS m / z = 420 (M+H).

[0293] Step 6.2-(4-(4-((2,6-Dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin- 1-yl)acetic acid hydrochloride. tert-Butyl 2-(4-(4-((2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)piperidin-1-yl)acetate (347 mg, 0.827 mmol, 1.0 equiv) was treated with 4M HCl in dioxane (1.5 mL, 6.0 mmol, 7.3 equiv) in dichloromethane (4.0 mL) at reflux for 18 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure and dried under vacuum at 40 °C for 18 hours to give a white solid (158 mg, 53% yield). LCMS m / z = 386.2 (M+Na).

[0294] Step 7.3-((4-(1-(2-(4-(6-(5-(5-((R)-1-(3,5-Dichloropyridin-4-yl)ethoxy)- 1H-indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)piperidin-1-yl)-2- oxoethyl)piperidin-4-yl)-3-fluorophenyl)amino)piperidine-2,6-dione. [6-[5-[5-[(1R)-1-(3,5- dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]heptan-2-yl]-(4- piperidyl)methanone (55 mg, 0.093 mmol, 1.0 equiv) was treated with 2-(4-(4-((2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperidin-1-yl)acetic acid hydrochloride (37 mg, 0.093 mmol, 1.0 equiv), N,N-diisopropylethylamine (41 mg, 0.32 mmol, 3.4 equiv) and propylphosphonic anhydride (50% w / w solution in ethyl acetate, 30 mg, 0.093 mmol, 1.0 equiv) in N,N-dimethylformamide (1.0 mL) at room temperature for 18 hours. The reaction was diluted with dimethyl sulfoxide (1.0 mL) and purified directly on a Biotage automated chromatography system (RediSep Rf GOLD 100 g HP C18 column), eluting with a gradient of 0 to 100% acetonitrile in water. The product containing fractions were combined and lyophilized to give a white solid (17 mg, 20% yield). LCMS m / z = 937, 939 (M+H); 1H - 132 -4896-4398-0599.1120039.000146 | TYRA.037PCT NMR (400 MHz, DMSO-d6) δ = 13.01 (br s, 1H), 10.76 (br s, 1H), 8.59 (s, 2H), 8.52 (d, J = 2.0 Hz, 1H), 7.87 (dd, J = 2.0, 8.6 Hz, 1H), 7.46 (d, J = 9.0 Hz, 1H), 7.17 (s, 1H), 7.09 (dd, J = 2.0, 9.0 Hz, 1H), 6.97 (t, J = 8.7 Hz, 1H), 6.55 (d, J = 8.7 Hz, 1H), 6.50-6.41 (m, 2H), 6.11 (q, J = 6.5 Hz, 1H), 5.99 (d, J = 7.8 Hz, 1H), 4.42 (s, 2H), 4.36-4.26 (m, 2H), 4.17 (s, 4H), 4.14-4.05 (m, 3H), 3.26-3.20 (m, 1H), 3.10-3.00 (m, 2H), 2.89 (br d, J = 9.8 Hz, 2H), 2.74 (ddd, J = 5.3, 12.1, 17.5 Hz, 1H), 2.68-2.52 (m, 4H), 2.14-2.02 (m, 3H), 1.86 (dq, J = 4.6, 12.2 Hz, 1H), 1.76 (d, J = 6.6 Hz, 3H), 1.73-1.48 (m, 7H), 1.38-1.26 (m, 1H). Example 28.2-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]ethyl 6-[5- [5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6- diazaspiro[3.3]-heptane-2-carboxylate. Step 3 Step 4Step 1 Step 2Example 28

[0295] Step 1. (E)-3-(4-(2-Ethoxyvinyl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione. [1,1'-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) (290 mg, 0.44 mmol, 0.1 equiv) and cesium fluoride (1.35 g, 8.87 mmol, 2.0 equiv) were sequentially added to a solution of 3-(4-bromo- 3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (1.5 g, 4.44 mmol, 1.0 equiv) and 2- [(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.05 g, 5.32 mmol, 1.2 equiv) at room temperature in a mixture of N,N-dimethylformamide (48 mL) and water (12 mL) The mixture was sparged with nitrogen for 10 minutes and then heated at 80 °C for 12 hours. - 133 - 4896-4398-0599.1120039.000146 | TYRA.037PCT After cooling to room temperature, the reaction was diluted with ethyl acetate (100 mL), filtered through Celite (5 g), which was rinsed with ethyl acetate (100 mL). The filtrate was washed with water (3 x 50 mL). The aqueous layer was extracted with ethyl acetate (150 mL), and washed with water (2 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (Sorbtech 80 g silica gel column), eluting with a gradient of 0 to 100% ethyl acetate in hexanes to give an off-white solid (1.2 g, 82% yield). LCMS m / z = 330.1 (M+H).

[0296] Step 2.2-(1-(2,6-Dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)acetaldehyde. Formic acid (12 mL) was added to 3-[4-[(E)-2- ethoxyvinyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (1.2 g, 3.64 mmol, 1.0 equiv) and the mixture was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure and the residue was purified on a Biotage automated chromatography system (RediSep Rf GOLD 100 g HP C18 column), eluting with a gradient of 0 to 100% acetonitrile in water. The product containing fractions were combined and lyophilized to give a white solid (580 mg, 53% yield). LCMS m / z = 302.1 (M+H).

[0297] Step 3.3-(4-(2-Hydroxyethyl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione. Sodium cyanoborohydride (295 mg, 4.65 mmol, 5.0 equiv) was added to a solution of 2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-4-yl)acetald (280 mg, 0.93 mmol, 1.0 equiv) in tetrahydrofuran (15 mL) at room temperature. Additional sodium cyanoborohydride was added at 3 hours (295 mg, 4.65 mmol, 5.0 equiv) and 16 hours sodium cyanoborohydride (295 mg, 4.65 mmol, 5.0 equiv) and then stirred for 24 hours. The reaction mixture was filtered through Celite (2 g), which was rinsed with tetrahydrofuran (25 mL). The filtrate was concentrated under reduced pressure and the residue was purified on a Biotage automated chromatography system (Sorbtech 12 g silica gel column), eluting with a gradient of 50 to 100% ethyl acetate in hexanes, then 10% methanol in dichloromethane to give a white solid (69 mg, 24% yield). LCMS m / z = 304.1 (M+H).

[0298] Step 4.2-(1-(2,6-Dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)ethyl 6-(5-(5-((R)-1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazol-3- yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate. A solution of 1,1’- carbonyldiimidazole (55 mg, 0.34 mmol, 1.5 equiv) in tetrahydrofuran (1 mL) was added to a - 134 -4896-4398-0599.1120039.000146 | TYRA.037PCT solution of 3-(4-(2-hydroxyethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1- yl)piperidine-2,6-dione (69 mg, 0.23 mmol, 1.0 equiv) in a 1 to 1 mixture of tetrahydrofuran and N,N-dimethylformamide (6 mL) at 0 °C. The mixture was warmed to room temperature and stirred for 16 hours to give 2-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4- yl]ethyl imidazole-1-carboxylate. The mixture was then added to a solution 3-[6-(2,6- diazaspiro[3.3]heptan-2-yl)-3-pyridyl]-5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H- indazole (110 mg, 0.23 mmol, 1.0 equiv) in N,N-dimethylformamide (2 mL) at room temperature and stirred for 16 hours. The reaction was purified on a Biotage automated chromatography system (RediSep Rf GOLD 100 g HP C18 column), eluting with a gradient of 0 to 100% acetonitrile in water. The product containing fractions were combined and lyophilized to give an off-white solid (30 mg, 16% yield). LCMS m / z = 810.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ = 13.00 (br s, 1H), 11.09 (br s, 1H), 8.59 (s, 2H), 8.51 (d, J = 2.0 Hz, 1H), 7.86 (dd, J = 2.1, 8.6 Hz, 1H), 7.46 (d, J = 9.0 Hz, 1H), 7.16 (s, 1H), 7.09 (dd, J = 2.1, 9.0 Hz, 1H), 7.06-6.98 (m, 2H), 6.97-6.92 (m, 1H), 6.52 (d, J = 8.7 Hz, 1H), 6.11 (q, J = 6.8 Hz, 1H), 5.38 (dd, J = 5.4, 12.6 Hz, 1H), 4.21 (br t, J = 6.9 Hz, 2H), 4.17-4.06 (m, 8H), 3.60 (s, 3H), 3.25-3.20 (m, 2H), 2.95-2.84 (m, 1H), 2.78-2.58 (m, 2H), 2.06-1.97 (m, 1H), 1.76 (d, J = 6.6 Hz, 3H). Example 29.3-[6-[4-[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3- yl]-2-pyridyl]-2,6-diazaspiro[3.3]-heptane-2-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4- hydroxy-1-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione. - 135 -4896-4398-0599.1120039.000146 | TYRA.037PCT Step 3Step 4 Example 29 Step 1Step 2

[0299] Step 1. tert-Butyl 2-(1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H- indazol-6-yl)-4-hydroxypiperidin-4-yl)acetate. A mixture of 6-bromo-3-(2,6-dibenzyloxy-3- pyridyl)-1-methyl-indazole (700 mg, 1.4 mmol, 1 equiv), tert-butyl 2-(4-hydroxy-4- piperidyl)acetate (421 mg, 1.2 mmol, 1.4 equiv) and cesium carbonate (1.4 g, 4.2 mmol, 3.0 equiv) in 1,4-dioxane (5.5 mL) was sparged with argon for 10 minutes then treated with 2- dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (65 mg, 0.14 mmol, 0.1 equiv) and methanesulfonato(2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl)(2'- methylamino-1,1'-biphenyl-2-yl)palladium(II) (119 mg, 0.15 mmol, 0.1 equiv). The mixture was sparged again with argon for 5 minutes and then heated at 100 ºC for 3 hours. The reaction mixture was cooled to room temperature, diluted with aqueous sodium carbonate (50 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with saturated brine (30 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (40 g Yamazen column), eluting with a gradient of 0 to 50% ethyl acetate in hexanes to give a light-brown oil (760 mg, 85% yield). LCMS m / z = 635 (M-H).

[0300] Step 2. tert-Butyl 2-(1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6- yl)-4-hydroxypiperidin-4-yl)acetate. A mixture of tert-butyl 2-(1-(3-(2,6- bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidin-4-yl)acetate (760 - 136 - 4896-4398-0599.1120039.000146 | TYRA.037PCT mg, 1.2 mmol, 1 equiv), 20% palladium hydroxide on carbon (800 mg, 1.1 mmol, 1 equiv) and triethylamine (0.4 mL, 2.9 mmol, 2.4 equiv) in a mixture of 1,4-dioxane (35 mL) and ethanol (35 mL) was hydrogenated at 50 psi at room temperature for 20 hours. The mixture was filtered through a pad of Celite, which was washed with 5% ethanol in dichloromethane (3 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (16 g Yamazen column), eluting with a gradient of 0 to 75% ethyl acetate in hexanes to give a colorless oil (550 mg, 100% yield). LCMS m / z = 455 (M-H).

[0301] Step 3.2-(1-(3-(2,6-Dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-4- hydroxypiperidin-4-yl)acetic acid HCl. A stirred solution of tert-butyl 2-(1-(3-(2,6- dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidin-4-yl) (88 mg, 0.19 mmol, 1 equiv) in 1,4-dioxane (1.5 mL) was cooled to 5 ºC and treated with 4M HCl in dioxane (5.4 mL, 10.8 mmol, 112 equiv). The mixture was stirred at room temperature for 82 hours. The reaction mixture was concentrated under reduce pressure and then diluted with THF (4 mL) and acetonitrile (2 mL). Additional 4M HCl in dioxane was added (1.5 mL, 6 mmol, 30 equiv) and the reaction was heated at 50 ºC for 7 hours. The reaction mixture was cooled to room temperature, then concentrated under reduced pressure to give a light-brown solid as the HCl salt (220 mg, >100% yield), which was used directly in the next step. LCMS m / z = 399 (M-H).

[0302] Step 4.3-[6-[4-[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H- indazol-3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]-heptane-2-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4- hydroxy-1-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione. Propylphosphonic anhydride solution (50% w / w in ethyl acetate, 0.14 mL, 0.24 mmol, 2 equiv) was added to a mixture of 2-(1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidin- 4-yl)acetic acid HCl (56 mg, 0.13 mmol, 1.1 equiv), [6-[5-[5-[(1R)-1-(3,5-dichloro-4- pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]heptan-2-yl]-(4- piperidyl)methanone (69 mg, 0.12 mmol, 1 equiv) and triethylamine (0.28 mL, 1.98 mmol, 17 equiv) in N,N-dimethylformamide (3 mL) at room temperature. The mixture was stirred at room temperature for 2 hours then concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (100 g RediSep Gold, C18 column), eluting with a gradient of 0 to 100% acetonitrile in water to give a white solid after lyophilization (22 mg, 19% yield). LCMS m / z = 976.3 (M+H); 1H NMR (400 MHz, DMSO- - 137 -4896-4398-0599.1120039.000146 | TYRA.037PCT d6) δ = 12.99 (s, 1H), 10.83 (s, 1H), 8.59 (s, 2H), 8.52 (s, 1H), 7.87 (dd, J = 1.7, 8.7 Hz, 1H), 7.46 (dd, J = 5.3, 8.9 Hz, 2H), 7.17 (s, 1H), 7.09 (d, J = 9.1 Hz, 1H), 6.91 (br d, J = 9.2 Hz, 1H), 6.84 (s, 1H), 6.54 (d, J = 8.7 Hz, 1H), 6.11 (q, J = 6.6 Hz, 1H), 5.03 (s, 1H), 4.42 (s, 3H), 4.24 (dd, J = 5.1, 9.0 Hz, 1H), 4.17 (s, 4H), 4.10-4.00 (m, 3H), 3.88 (s, 3H), 3.54-3.46 (m, 2H), 3.16 (br t, J = 10.5 Hz, 2H), 3.07 (br t, J = 12.1 Hz, 1H), 2.70-2.52 (m, 5H), 2.35- 2.25 (m, 1H), 2.20-2.11 (m, 1H), 1.81-1.62 (m, 10H), 1.49 (q, J = 11.2 Hz, 1H), 1.39-1.29 (m, 1H). Example 31.1-[6-[4-[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3- yl]-2-pyridyl]-2,6-diazaspiro[3.3]-heptane-2-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4- hydroxy-1-piperidyl]-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione.

[0303] Step 1. tert-Butyl 2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1- methyl-1H-indazol-6-yl)-4-hydroxypiperidin-4-yl)acetate.1-(6-Bromo-1-methyl-indazol-3- yl)hexahydropyrimidine-2,4-dione (500 mg, 1.55 mmol, 1.0 equiv), tert-butyl 2-(4-hydroxy- 4-piperidyl)acetate (400 mg, 1.86 mmol, 1.2 equiv) and cesium carbonate (958 mg, 2.94 mmol, 1.9 equiv) in 1,4-dioxane (5.5 mL) was sparged with nitrogen for 15 minutes. Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (43 mg, 0.093 mmol, 0.06 equiv) and methanesulfonato(2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl)(2'- methylamino-1,1'-biphenyl-2-yl)palladium(II) (132 mg, 0.155 mmol, 0.1 equiv) were added and the reaction sparged with nitrogen for 5 additional minutes. After heating at 100 °C for 24 hours, the reaction was cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with water (20 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (Sorbtech 40 g silica gel column) eluting with a gradient of 0 to 100% ethyl acetate in hexanes to give an off-white solid (175 mg, 25% yield). LCMS m / z = 458.2 (M+H).

[0304] Step 2.2-(1-(3-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-6-yl)-4-hydroxypiperidin-4-yl)acetic acid. tert-Butyl 2-(1-(3-(2,4- - 138 -4896-4398-0599.1120039.000146 | TYRA.037PCT dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidin-4- yl)acetate (175 mg, 0.383 mmol, 1.0 equiv) was treated with 4M HCl in dioxane (10.5 mL, 42.0 mmol, 110 equiv) at 50 °C for 6 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure and dried under vacuum at 40 °C for 18 hours to give an off-white solid (175 mg, >100% yield). LCMS m / z = 402.2 (M+H).

[0305] Step 3. (R)-1-(6-(4-(2-(4-(6-(5-(5-(1-(3,5-Dichloropyridin-4-yl)ethoxy)- 1H-indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)piperidin-1-yl)-2- oxoethyl)-4-hydroxypiperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione. [6-[5-[5-[(1R)-1-(3,5-Dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]heptan-2-yl]-(4-piperidyl)methanone (50 mg, 0.084 mmol, 1.0 equiv) was treated with 2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-6-yl)-4-hydroxypiperidin-4-yl)acetic acid (37 mg, 0.084 mmol, 1.0 equiv), N,N- diisopropylethylamine (37 mg, 0.29 mmol, 3.4 equiv) and propylphosphonic anhydride (50% w / w solution in ethyl acetate, 27 mg, 0.084 mmol, 1.0 equiv) in N,N-dimethylformamide (1.0 mL) at room temperature for 18 hours. The reaction was diluted with dimethyl sulfoxide (1.0 mL) and purified directly on a Biotage automated chromatography system (RediSep Rf GOLD 100 g HP C18 column), eluting with a gradient of 0 to 100% acetonitrile in water. The product containing fractions were combined and lyophilized to give a white solid (19 mg, 23% yield). LCMS m / z = 975.8 (M+H); 1H NMR (400 MHz, DMSO-d6) δ = 12.98 (br s, 1H), 10.48 (br s, 1H), 8.59 (s, 2H), 8.52 (d, J = 2.0 Hz, 1H), 7.87 (dd, J = 2.3, 8.6 Hz, 1H), 7.46 (br d, J = 9.0 Hz, 1H), 7.43 (br d, J = 9.0 Hz, 1H), 7.17 (d, J = 2.1 Hz, 1H), 7.09 (dd, J = 2.3, 9.0 Hz, 1H), 6.91 (dd, J = 1.7, 9.2 Hz, 1H), 6.82 (s, 1H), 6.54 (d, J = 8.6 Hz, 1H), 6.11 (q, J = 6.6 Hz, 1H), 5.03 (s, 1H), 4.49-4.35 (m, 3H), 4.17 (s, 4H), 4.08 (s, 2H), 4.04 (br d, J = 13.1 Hz, 1H), 3.95-3.83 (m, 5H), 3.57-3.46 (m, 2H), 3.17 (br t, J = 10.1 Hz, 2H), 3.07 (br t, J = 11.7 Hz, 1H), 2.73 (t, J = 6.7 Hz, 2H), 2.68-2.61 (m, 1H), 2.59-2.51 (m, 2H), 1.80-1.72 (m, 5H), 1.71-1.63 (m, 4H), 1.56-1.43 (m, 1H), 1.41-1.27 (m, 1H). Example 33.4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]-heptane-2-carbonyl]-N-[2-[2-(2,6-dioxo-3-piperidyl)-1,3- dioxo-isoindolin-4-yl]ethyl]piperidine-1-carboxamide. - 139 -4896-4398-0599.1120039.000146 | TYRA.037PCT Step 4Step 1Step 2Step 5 Step 6Example 33

[0306] (E)-2-(2,6-Dioxopiperidin-3-yl)-4-(2-ethoxyvinyl)isoindoline-1,3-dione. A 100 mL round bottomed flask was charged with 4-bromo-2-(2,6-dioxo-3- Example 33 piperidyl)isoindoline-1,3-dione (1.5 g, 4.45 mmol, 1 equiv), 2-[(E)-2-ethoxyvinyl]-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (1.06 g, 5.34 mol, 1.2 equiv), [1,1’-bis(di-tert- butylphosphino)ferrocene]dichloride (290 mg, 445 µmol, 0.1 equiv), and cesium fluoride (1.35 g, 8.9 mmol, 2 equiv), then N,N-dimethylformamide (48 mL) and water (12 mL) was added. The reaction was sparged with nitrogen for 10 minutes then heated at 80 °C for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water (80 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with water (100 mL) and saturated brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (Biotage Sfar HC 25 g column), eluting with a gradient of 0 to 100% ethyl acetate in hexanes to give a tan solid (1.6 g, 81% yield) after drying under vacuum at 40 °C for 10 hours. LCMS m / z = 329.1 (M+H).

[0307] Step 2.2-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)acetaldehyde. Formic acid (12 mL, 318 mmol, 87 equiv) was added to 2-(2,6-dioxo-3- piperidyl)-4-[(E)-2-ethoxyvinyl]isoindoline-1,3-dione (1.2 g, 3.65 mmol, 1 equiv) in a 150 mL round bottomed flask and the resulting suspension was stirred at room temperature for 2 hours. The volatiles were evaporated under reduced pressure. Toluene (50 mL) was added to - 140 - 4896-4398-0599.1120039.000146 | TYRA.037PCT the residue and the mixture was evaporated to dryness under reduced pressure to give an amber foam (1.5 g), which was used in the next step. LCMS m / z = 301.1 (M+H).

[0308] Step 3.2-(2,6-Dioxopiperidin-3-yl)-4-(2-hydroxyethyl)isoindoline-1,3- dione. Sodium cyanoborohydride (1.39 g, 22.15 mmol, 5 equiv) was added to a stirred solution of 2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetaldehyde (1.4 g, <3.6 mmol, 1 equiv) in THF (42 mL) at room temperature. After stirring at room temperature for 2 hours, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (Biotage Sfar 25 g column), eluting with a gradient of 50 to 100% ethyl acetate in hexanes to give a light yellow solid (620 mg, 56% yield over 2 steps). (LCMS m / z= 303.1 (M+H).

[0309] Step 4.2-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)ethyl methanesulfonate. Methanesulfonyl chloride (180 µL, 2.34 mmol, 1.2 equiv) and triethylamine (0.81 mL, 5.84 mmol, 3 equiv) were sequentially added to a solution of 2-(2,6- dioxopiperidin-3-yl)-4-(2-hydroxyethyl)isoindoline-1,3-dione (620 mg, 1.95 mmol, 1 equiv) in dichloromethane (5 mL) and THF (4 mL). A slurry was formed after addition of triethylamine. The reaction was stirred at room temperature for 17 hours. Water (30 mL) was added and the layers were separated. The aqueous layer was extracted with dichloromethane (2 x 15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (Biotage Sfar HC 10 g column), eluting with a gradient of 50 to 100% ethyl acetate in hexanes to give a white solid (385 mg, 50% yield) after drying at 40 °C under vacuum for 1 hour. LCMS m / z = 381.4 (M+H).

[0310] Step 5.4-(2-Azidoethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. Sodium azide (70 mg, 1.0 mmol, 1.2 equiv) was added to a solution of 2-(2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)ethyl methanesulfonate (335 mg, 0.88 mmol, 1 equiv) in N,N-dimethylformamide (1.4 mL) and the resulting suspension was stirred at 50 °C for 4 hours. The reaction was cooled to room temperature, poured into ice-water (15 mL) and extracted with ethyl acetate (3 x 35 mL). The combined organic layers were washed with water (40 mL) and saturated brine (40 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a light purple oil which solidified on standing to a tan solid (260 mg, 86% yield). LCMS m / z = 328.3 (M+H). - 141 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0311] Step 6.4-(2-Aminoethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. Polymer-bound triphenylphosphine (capacity 1.89 mmol / g, 520 mg, 0.98 mmol, 1.3 equiv) and water (70 µL, 3.88 mmol, 5 equiv) were sequentially added to a solution of 4-(2- azidoethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (260 mg, 0.75 mmol, 1 equiv) in THF (5.5 mL) at room temperature. After stirring at room temperature for 8 hours, the reaction mixture was filtered through a Celite pad (2 g). The filtrate was concentrated under reduced pressure to give an off-white solid (70 mg, 31% yield). LCMS m / z = 302.0 (M+H).

[0312] Step 7.4-(6-(5-(5-((R)-1-(3,5-Dichloropyridin-4-yl)ethoxy)-1H-indazol-3- yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)-N-(2-(2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4-yl)ethyl)piperidine-1-carboxamide. A solution of 1,1′- carbonyldiimidazole (20 mg, 0.12 mmol, 1.5 equiv) in THF (0.2 mL) was added at 0 °C under a nitrogen atmosphere to a solution of 4-(2-aminoethyl)-2-(2,6-dioxopiperidin-3- yl)isoindoline-1,3-dione (40 mg, 80 µmol, 1 equiv) in THF (0.3 mL). After 10 minutes the ice bath was removed, and the reaction mixture was stirred at room temperature for 3 hours. LCMS analysis showed no starting material and formation of N-[2-[2-(2,6-dioxo-3- piperidyl)-1,3-dioxo-isoindolin-4-yl]ethyl]imidazole-1-carboxamide (LCMS m / z = 396.0 (M+H)). The reaction mixture was added dropwise in portions (5 x 0.1 mL portions; each addition was followed by 45 minutes stirring without addition) to a stirred solution of [6-[5- [(4E)-4-[2-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]prop-2-enylidene]-1,5-dihydropyrazol-3- yl]-2-pyridyl]-2,6-diazaspiro[3.3]heptan-2-yl]-(4-piperidyl)methanone (60 mg, 80 µmol, 1 equiv) in N,N-dimethylformamide (0.5 mL) at room temperature. After the addition was complete, the reaction was stirred for 3 hours at room temperature. The reaction mixture was diluted with water (5 mL) and extracted with 5% methanol in dichloromethane (3 x 20 mL). The combined organic layers were washed with water (50 mL) and saturated brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (RediSep Gold C1830 g column), eluting with a gradient of 0 to 40% acetonitrile in water to give a light yellow solid (22 mg, 6% yield over 2 steps). LCMS m / z = 919.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ = 13.00 (br s, 1H), 11.09 (br s, 1H), 8.59 (s, 2H), 8.52 (d, J = 1.8 Hz, 1H), 7.87 (dd, J = 2.3, 8.6 Hz, 1H), 7.81-7.74 (m, 2H), 7.62 (dd, J = 2.2, 6.5 Hz, 1H), 7.46 (d, J = 9.0 Hz, 1H), 7.17 (s, 1H), 7.09 (dd, J = 2.2, 9.0 Hz, 1H), 6.59-6.48 (m, 2H), 6.11 (q, J = 6.7 Hz, 1H), 5.14 (dd, J = 5.4, 12.9 Hz, 1H), 4.40 (s, 2H), 4.17 (s, 4H), 4.07 (s, 2H), 3.89 (br d, J = 13.0 Hz, 2H), - 142 -4896-4398-0599.1120039.000146 | TYRA.037PCT 3.40-3.34 (m, 2H), 3.25-3.14 (m, 2H), 2.96-2.85 (m, 1H), 2.70-2.53 (m, 4H), 2.43-2.31 (m, 1H), 2.09-2.02 (m, 1H), 1.76 (d, J = 6.7 Hz, 3H), 1.55 (br d, J = 11.1 Hz, 2H), 1.40-1.28 (m, 2H). Example 34.6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- N-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]prop-2-ynyl]-2,6- diazaspiro[3.3]heptane-2-carboxamide.

[0313] Step 1. tert-Butyl (3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)prop-2-yn-1-yl)carbamate. A mixture of 4-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline- 1,3-dione (250 mg, 0.75 mmol, 1.0 equiv), N-Boc-propargylamine (230 mg, 1.5 mmol, 2.0 equiv), copper(I) iodide (28 mg, 0.15 mmol, 0.2 equiv), bis(triphenylphosphine)palladium chloride (52 mg, 0.07 mmol, 0.1 equiv) and triethylamine (1.6 mL, 11.0 mmol, 15 equiv) was sparged with nitrogen for 10 minutes. The reaction mixture was heated at 80 °C for 22 hours. After cooling to room temperature, the reaction was diluted with water (60 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with water (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure onto silica gel (3 g). The residue was purified on a Biotage automated chromatography system (Biotage Sfar 10 g, 20 µm silica gel), eluting with a gradient of 0 to 100% ethyl acetate in hexanes to give a pale yellow solid (157 mg, 52% yield). LCMS m / z = 434 (M+Na).

[0314] Step 2.4-(3-Aminoprop-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione bis(trifluoroacetic acid) salt. A mixture of tert-butyl (3-(2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1-yl)carbamate (109 mg, 0.26 mmol, 1.0 equiv) and trifluoroacetic acid (4.0 mL, 53.0 mmol, 200 equiv) in dichloromethane (4.0 mL) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. - 143 -4896-4398-0599.1120039.000146 | TYRA.037PCT Dichloromethane (4.0 mL) was added then solvent was removed under reduced pressure to give a tan solid (142 mg, 100% yield), which was used directly in the next step. LCMS m / z = 312 (M+H, free base).

[0315] Step 3.6-(5-(5-((R)-1-(3,5-Dichloropyridin-4-yl)ethoxy)-1H-indazol-3- yl)pyridin-2-yl)-N-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1-yl)- 2,6-diazaspiro[3.3]heptane-2-carboxamide. A solution of 4-(3-aminoprop-1-yn-1-yl)-2-(2,6- dioxopiperidin-3-yl)isoindoline-1,3-dione bis(trifluoroacetic acid) salt (142 mg, 0.27 mmol, 1.0 equiv), N,N-diisopropylethylamine (0.9 mL, 5.3 mmol, 20 equiv), and bis(succinimidoyl)carbonate (68 mg, 0.27 mmol, 1.0 equiv) in dioxane (4.0 mL) was stirred at room temperature for 16 hours. LCMS analysis confirmed the formation of the succinimidoylcarbamate. 3-[6-(2,6-Diazaspiro[3.3]-heptan-2-yl)-3-pyridyl]-5-[(1R)-1-(3,5- dichloro-4-pyridyl)ethoxy]-1H-indazole (128 mg, 0.27 mmol, 1.0 equiv) was added and the reaction mixture was heated at 80 °C for 20 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give a dark brown oil. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were washed with water (3 x 5 mL). The insoluble material was filtered and washed with 2-methyltetrahydrofuran (15 mL). The organic filtrates were dried over sodium sulfate, filtered, and concentrated under reduced pressure onto Celite (2.5 g). The residue was purified on a Biotage automated chromatography system (Biotage Sfar 10 g, 20 µm silica gel), eluting with a gradient of 0 to 100% methanol in ethyl acetate to give a tan solid (5 mg, 2% yield). LCMS m / z = 818, 820 (M+H); 1H NMR (400 MHz, DMSO-d6) δ = 12.99 (s, 1H), 11.14 (s, 1H), 8.59 (s, 2H), 8.51 (d, J = 2.2 Hz, 1H), 7.94-7.82 (m, 4H), 7.45 (d, J = 9.0 Hz, 1H), 7.19-7.14 (m, 1H), 7.09 (dd, J = 2.2, 8.9 Hz, 1H), 7.02 (t, J = 5.7 Hz, 1H), 6.53 (d, J = 8.7 Hz, 1H), 6.11 (q, J = 6.5 Hz, 1H), 5.15 (dd, J = 5.4, 12.8 Hz, 1H), 4.19-4.10 (m, 6H), 4.07 (s, 4H), 2.96-2.87 (m, 1H), 2.65-2.55 (m, 2H), 2.12-2.04 (m, 1H), 1.76 (d, J = 6.6 Hz, 3H). Example 37.1-[6-[1-[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3- yl]-2-pyridyl]-2,6-diazaspiro[3.3]-heptane-2-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4- piperidyl]-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione. - 144 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0316] Step 1.3-((6-Bromo-1-methyl-1H-indazol-3-yl)amino)propanoic acid.6- Bromo-1-methyl-indazol-3-amine (15.00 g, 66.35 mmol, 1.0 equiv) and tetrabutylammonium bromide (2.14 g, 6.64 mmol, 0.10 equiv) were dissolved in 2M HCl (150 mL, 300 mmol, 4.5 equiv) and heated to 55 °C. Acrylic acid (6.8 mL, 99.5 mmol, 1.5 equiv) was added dropwise over 20 minutes. After heating at 100 °C for 20 hours, the reaction was cooled to room temperature, diluted with water (300 mL) and adjusted to pH 7 with saturated sodium bicarbonate (100 mL). The resulting solid was filtered, washed with water (30 mL) and dried under vacuum at 40 °C overnight to give a tan solid. (17.62 g, 89% yield). LCMS m / z = 298 / 300 (M+H).

[0317] Step 2.1-(6-Bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione.3-[(6-Bromo-1-methyl-indazol-3-yl)amino]propanoic acid (17.62 g, 59.10 mmol, 1.0 equiv) and sodium cyanate (6.92 g, 106 mmol, 1.8 equiv) in acetic acid (112 mL) was heated at 100 °C for 72 hours. The reaction was cooled to room temperature and the resulting solid filtered, washed with water (120 mL) and dried under vacuum at 40 °C for 24 hours to give a tan solid (7.02 g, 37% yield). LCMS m / z = 323 / 325 (M+H).

[0318] Step 3. tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl- 1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate.1-(6-Bromo-1-methyl-1H-indazol- 3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.89 g, 5.85 mmol, 1.0 equiv), tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (2.35 g, 7.60 mmol, 1.3 equiv) and sodium acetate (1.44 g, 17.6 mmol, 3.0 equiv) in 1,4-dioxane (25.0 mL) and water (5.0 mL) were sparged with nitrogen for 10 minutes. [1,1′- - 145 -4896-4398-0599.1120039.000146 | TYRA.037PCT bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (478 mg, 0.585 mmol, 0.10 equiv) was added and the reaction sparged with nitrogen for 10 additional minutes then heated at 90 °C for 23 hours. The reaction was cooled to room temperature, concentrated under reduced pressure and the residue was purified on a Biotage automated chromatography system (Sorbtech 80 g silica gel column), eluting with a gradient of 0 to 100% ethyl acetate in hexanes to give a yellow solid (1.83 g, 74% yield). LCMS m / z = 426 (M+H).

[0319] Step 4. tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl- 1H-indazol-6-yl)piperidine-1-carboxylate. tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin- 1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.83 g, 4.30 mmol, 1 equiv), acetic acid (0.25 mL, 4.3 mmol, 1 equiv) and 10% palladium on carbon (458 mg, 0.430 mmol, 0.1 equiv) in ethanol (30.0 mL) and dichloromethane (10.0 mL) was hydrogenated at 50 psi for 18 hours. The reaction was filtered through celite (5 g), which was rinsed with a mixture of dichloromethane (5 mL) and ethanol (50 mL). The filtrate was concentrated under reduced pressure to give an off-white solid (1.60 g, 87% yield).

[0320] Step 5.1-(1-Methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione. tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-6-yl)piperidine-1-carboxylate (1.60 g, 3.74 mmol, 1.0 equiv) was treated with 4M HCl in dioxane (20.0 mL, 80.0 mmol, 21.4 equiv) in dichloromethane (20 mL) at room temperature for 2.5 hours. The reaction was concentrated under reduced pressure and dissolved in acetonitrile (50 mL), and then adjusted to pH 7 with saturated sodium bicarbonate. The resulting solid was filtered and dried under vacuum at 35 ºC overnight to give a tan solid (770 mg, 63% yield). LCMS m / z = 328 (M+H).

[0321] Step 6. tert-Butyl 2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1- methyl-1H-indazol-6-yl)piperidin-1-yl)acetate.1-(1-Methyl-6-(piperidin-4-yl)-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (400 mg, 1.22 mmol, 1.0 equiv) was treated with tert-butyl 2-bromoacetate (0.20 mL, 1.22 mmol, 1.0 equiv) and triethylamine (0.70 mL, 4.89 mmol, 4.0 equiv) in N,N-dimethylformamide (6.0 mL) at room temperature for 18 hours. The reaction was diluted with ethyl acetate (20 mL) and cold water (50 mL). The layers were separated, and the aqueous layer extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over sodium sulfate then concentrated under reduced pressure to give a tan solid (288 mg, 53% yield). LCMS m / z = 442 (M+H). - 146 -4896-4398-0599.1120039.000146 | TYRA.037PCT

[0322] Step 7.2-(4-(3-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-6-yl)piperidin-1-yl)acetic acid hydrochloride. tert-Butyl 2-(4-(3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)acetate (288 mg, 0.652 mmol, 1.0 equiv) was treated with 4M HCl in dioxane (2.45 mL) in dichloromethane (15.0 mL) at reflux overnight. After cooling to room temperature, the reaction was concentrated under reduced pressure then dried under vacuum at 40 °C overnight to give a yellow solid (333 mg, >100% yield). LCMS m / z = 386.2 (M+H).

[0323] Step 8. (R)-1-(6-(1-(2-(4-(6-(5-(5-(1-(3,5-Dichloropyridin-4-yl)ethoxy)- 1H-indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)piperidin-1-yl)-2- oxoethyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione. [6- [5-[5-[(1R)-1-(3,5-Dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6- diazaspiro[3.3]heptan-2-yl]-(4-piperidyl)methanone (49 mg, 0.083 mmol, 1.0 equiv) was treated with 2-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6- yl)piperidin-1-yl)acetic acid hydrochloride (35 mg, 0.083 mmol, 1.0 equiv), N,N- diisopropylethylamine (36 mg, 0.28 mmol, 3.4 equiv) and propylphosphonic anhydride (50% w / w solution in ethyl acetate, 26 mg, 0.083 mmol, 1.0 equiv) in N,N-dimethylformamide (1.0 mL) at room temperature for 18 hours. The reaction was diluted with dimethyl sulfoxide (1.0 mL) and purified directly on a Biotage automated chromatography system (RediSep Rf GOLD 100 g HP C18 column) eluting with a gradient of 0 to 100% acetonitrile in water (each containing 0.1% formic acid). The fractions containing clean product were combined and lyophilized to give a white solid (26 mg, 31% yield) as the formate salt. LCMS m / z = 848.2 (M+H); 1H NMR (400 MHz, DMSO-d6) δ = 12.97 (s, 1H), 11.07 (br s, 1H), 8.59 (s, 2H), 8.50 (s, 1H), 7.84 (br d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.45 (d, J = 8.9 Hz, 1H), 7.36 (s, 1H), 7.26 (br d, J = 8.6 Hz, 1H), 7.16 (s, 1H), 7.09 (br d, J = 8.9 Hz, 1H), 6.50 (d, J = 8.7 Hz, 1H), 6.10 (q, J = 6.5 Hz, 1H), 5.08 (dd, J = 5.3, 12.8 Hz, 1H), 4.08 (s, 2H), 3.91 (s, 2H), 3.63 (br s, 2H), 3.58-3.43 (m, 6H), 3.42-3.35 (m, 1H), 2.95-2.82 (m, 1H), 2.62- 2.52 (m, 2H), 2.47-2.43 (m, 3H), 2.07-1.97 (m, 1H), 1.76 (d, J = 6.5 Hz, 3H). The following experimental are representative examples of the invention. - 147 -4896-4398-0599.1120039.000146 | TYRA.037PCTExample 44.5-[[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]- 2-pyridyl]piperazine-1-carbonyl]-1-piperidyl]-2-oxo-ethyl]amino]-2-(2,6-dioxo-3- piperidyl)isoindoline-1,3-dione

[0324] Step 1. tert-Butyl (R)-4-(4-(5-(5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H- indazol-3-yl)pyridin-2-yl)piperazine-1-carbonyl)piperidine-1-carboxylate. Triethylamine (1.1 mL, 7.67 mmol, 8.0 equiv) and 50% propylphosphonic anhydride in ethyl acetate (2.3 mL, 3.84 mmol, 4.0 equiv) were sequentially added to a solution of 5-[(1R)-1-(3,5-dichloro-4- pyridyl)ethoxy]-3-(6-piperazin-1-yl-3-pyridyl)-1H-indazole (450 mg, 0.96 mmol, 1.0 equiv) and 1-tert-butoxycarbonylpiperidine-4-carboxylic acid1 (264 mg, 1.15 mmol, 1.2 equiv) in N,N-dimethylformamide (17 mL) at room temperature. The mixture was stirred at room temperature for 70 hours at which point LCMS analysis indicated the reaction was complete. The mixture was diluted with ethyl acetate (200 mL), washed with water (3 x 40 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give an orange oil (764 mg, quantitative yield). LCMS m / z = 680.2 (M+H).

[0325] Step 2. [4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]- 2-pyridyl]piperazin-1-yl]-(4-piperidyl)methanone. tert-Butyl (R)-4-(4-(5-(5-(1-(3,5- dichloropyridin-4-yl)ethoxy)-1H-indazol-3-yl)pyridin-2-yl)piperazine-1-carbonyl)piperidine- 1-carboxylate (900 mg, 1.32 mmol, 1.0 equiv) in dichloromethane (5 mL) was treated with trifluoroacetic acid (5 mL) at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure then diluted with ethyl acetate (100 mL). The mixture was treated with 1M sodium hydroxide (30 mL), dropwise and 2M sodium hydroxide (20 mL) to adjust the aqueous layer to pH ~9. The organic layer was washed with 2M sodium hydroxide solution (10 mL) and 3M sodium hydroxide solution (10 mL). The aqueous layers were combined, diluted with 3M sodium hydroxide (10 mL) and extracted with ethyl acetate (100 mL). All the organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (RediSep Rf GOLD 100 g HP C18 column), eluting with a gradient - 148 -4896-4398-0599.1120039.000146 | TYRA.037PCT of 0 to 100% acetonitrile in water. The product containing fractions were lyophilized to give an off-white solid (350 mg, 46% yield). LCMS m / z = 580.1 (M+H); 1H NMR (400 MHz, DMSO-d6) δ = 13.03 (br s, 1H), 8.60 (s, 2H), 8.56 (d, J = 2.1 Hz, 1H), 7.89 (dd, J = 2.4, 8.9 Hz, 1H), 7.46 (d, J = 9.0 Hz, 1H), 7.16 (d, J = 2.1 Hz, 1H), 7.09 (dd, J = 2.3, 9.0 Hz, 1H), 7.00 (d, J = 8.9 Hz, 1H), 6.11 (q, J = 6.6 Hz, 1H), 3.70 - 3.53 (m, 8H), 2.94 (br d, J = 12.0 Hz, 2H), 2.74 (br t, J = 11.2 Hz, 1H), 2.60 - 2.51 (m, 2H), 1.76 (d, J = 6.6 Hz, 3H), 1.61 - 1.41 (m, 4H).

[0326] Step 3.5-[[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H- indazol-3-yl]-2-pyridyl]piperazine-1-carbonyl]-1-piperidyl]-2-oxo-ethyl]amino]-2-(2,6- dioxo-3-piperidyl)isoindoline-1,3-dione. Triethylamine (0.1 mL, 0.69 mmol, 8.0 equiv) and 50% propylphosphonic anhydride in ethyl aceta...

Claims

120039.000146 | TYRA.037PCT What is claimed is:

1. A compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein: n is 1, 2, or 3; m is 0, 1, 2, or 3; each R1is, independently, H, CN, or optionally substituted C1-6alkyl; or two R1groups attached to the same carbon atom, together with the carbon atom to which they are both attached form an optionally substituted 3-7 membered spirocycloalkyl or an optionally substituted 3-7 membered spiroheterocycloalkyl; or two R1groups attached to the same carbon atom, together with that carbon atom, form a carbonyl group (C=O); or two R1groups attached to different carbon atoms, together with the carbon atoms to which they are attached, form a 3-7 membered cycloalkyl; each R2is, independently H, CN, or optionally substituted C1-6alkyl; or two R2groups attached to the same carbon atom, together with the carbon atom to which they are both attached form an optionally substituted 3-7 membered spirocycloalkyl or an optionally substituted 3-7 membered spiroheterocycloalkyl; or two R2groups attached to the same carbon atom, together with that carbon atom, form a carbonyl group (C=O); or two R2groups attached to different carbon atoms, together with the carbon atoms to which they are attached, form a 3-7 membered cycloalkyl; or an R1group and an R2group are attached to form a 6-9 membered bridged bicyclic ring; - 302 -4896-4398-0599.1120039.000146 | TYRA.037PCT A is N or CH; Z is NR3or CR4R4’; R3is a bond to L; R4is H, F, CN, or optionally substituted C1-6alkyl; R4’is R3, OR3, NHR3, or -NR3(C1-3alkyl); or R4and R4’, together with the C atom to which they are both attached, form a substituted 3- to 7-membered heterocycloalkyl or a substituted 3- to 7-membered cycloalkyl, wherein the substituted 3- to 7- membered heterocycloalkyl or the substituted 3- to 7-membered cycloalkyl is substituted with one R3; Y is a 5-membered heteroaryl, 6-membered heteroaryl, or a 6-membered aryl; Q6and Q8are each, independently, N or CR5, wherein R5is H, halo, C1-3alkyl, C1- 3alkoxy, or cycloalkyl; D1is O or NRB, wherein RBis H or C1-3alkyl; R6is C1-6alkyl; R7is H, halo, C1-6alkyl, C1-6alkoxy, or cycloalkyl; L is a bivalent linker bound at one valence through bond R3and bound at the other valence to a carbon atom of Z2;CH or N; X3is bond or -NH-, provided that X2is CH when X3is -NH-; and R8to R12- 303 -4896-4398-0599.1120039.000146 | TYRA.037PCT are, independently, a bond to L, H, halo, C1-6alkyl, O-C1-6alkyl, CF3, or CN, wherein one of R8to R12is a bond to L.

2. The compound of claim 1, wherein n is 1, or n is 2, or n is 3.

3. The compound of claim 1, wherein m is 0, or m is 1, or m is 2, or m is 3.

4. The compound of any one of the preceding claims, wherein R1is H.

5. The compound of any one of claims 1-3, wherein R1is CN.

6. The compound of any one of claims 1-3, wherein R1is optionally substituted C1-6alkyl.

7. The compound of any one of the preceding claims, wherein R2is H.

8. The compound of any one of claims 1-6, wherein R2is CN.

9. The compound of any one of claims 1-6, wherein R2is optionally substituted C1-6alkyl.

10. The compound of any one of the preceding claims, wherein A is CH.

11. The compound of any one of claims 1-9, wherein A is N.

12. The compound of any one of the preceding claims, wherein Y is a 5-membered heteroaryl.

13. The compound of any one of claims 1-11, wherein Y is 6-membered heteroaryl.

14. The compound of any one of claims 1-11, wherein Y is 6-membered aryl.

15. The compound of any one of the preceding claims, wherein R7is H.

16. The compound of any one of claims 1-14, wherein R7is halo.

17. The compound of any one of claims 1-14, wherein R7is C1-6alkyl.

18. The compound of any one of claims 1-14, wherein R7is C1-6alkoxy.

19. The compound of any one of claims 1-14, wherein R7is cycloalkyl. - 304 -4896-4398-0599.1120039.000146 | TYRA.037PCT 20. The compound of any one of the preceding claims, wherein Q6is N.

21. The compound of any one of the preceding claims, wherein Q8is N.

22. The compound of any one of claims 1-20, wherein Q8is CR5.

23. The compound of any one of claims 1-19, 21 or 22, wherein Q6is CR5.

24. The compound of any one of claims 1-19, 22, or 23, wherein R5is H.

25. The compound of any one of claims 1-19, 22, or 23, wherein R5is halo.

26. The compound of any one of claims 1-19, 22, or 23, wherein R5is C1-3alkyl.

27. The compound of any one of claims 1-19, 22, or 23, wherein R5is C1-3alkoxy.

28. The compound of any one of claims 1-19, 22, or 23, wherein R5is cycloalkyl.

29. The compound of any one of the preceding claims, wherein Z2is.

30. The compound of any one of claims 1-28, wherein.

31. The compound of any one of claims 1-28, wherein Z2is. - 305 -4896-4398-0599.1120039.000146 | TYRA.037PCT 32. The compound of any one of claims 1-28, wherein Z2is.

33. The compound of any one of claims 1-28, wherein34. The compound of any one of claims 1-28, 31, 32, or 33, wherein X2is CH.

35. The compound of any one of claims 1-28, 31, 32, or 33, wherein X2is N.

36. The compound of any one of claims 1-28, or 33-35, wherein X3is a bond.

37. The compound of any one of claims 1-28, or 33-34, wherein X3is -NH-.

38. The compound of any one of claims 1-28, 31, or 32, wherein RAis H.

39. The compound of any one of claims 1-28, 31, or 32, wherein RAis C1-6alkyl.

40. The compound of any one of the preceding claims, wherein at least one of R8to R12is H.

41. The compound of any one of claims 1-39, wherein at least one of R8to R12is halo.

42. The compound of any one of claims 1-39, wherein at least one of R8to R12is C1-6alkyl.

43. The compound of any one of claims 1-39, wherein at least one of R8to R12is -OC1-6alkyl.

44. The compound of any one of claims 1-39, wherein at least one of R8to R12is CF3.

45. The compound of any one of claims 1-39, wherein at least one of R8to R12is CN.

46. The compound of any one of the preceding claims, wherein R8is a bond to L. - 306 -4896-4398-0599.1120039.000146 | TYRA.037PCT 47. The compound of any one of claims 1-45, wherein R9is a bond to L.

48. The compound of any one of claims 1-45, wherein R10is a bond to L.

49. The compound of any one of claims 1-45, wherein R11is a bond to L.

50. The compound of any one of claims 1-45, wherein R12is a bond to L.

51. The compound of any one of the preceding claims, wherein Z is NR3.

52. The compound of any one of claims 1-50, wherein Z is CR4R4’.

53. The compound of any one of claims 1-50 or 52, wherein R4is H.

54. The compound of any one of claims 1-50 or 52, wherein R4is F.

55. The compound of any one of claims 1-50 or 52, wherein R4is CN.

56. The compound of any one of claims 1-50 or 52, wherein R4is optionally substituted C1-6alkyl.

57. The compound of any one of claims 1-50 or 52-56, wherein R4’is R3.

58. The compound of any one of claims 1-50 or 52-56, wherein R4’is OR3.

59. The compound of any one of claims 1-50 or 52-56, wherein R4’is NHR3.

60. The compound of any one of claims 1-50 or 52-56, wherein R4’is -NR3(C1-3alkyl).

61. The compound of any one of claims 1-50 or 52, wherein R4and R4’together form an substituted 3- to 7-membered heterocycloalkyl that is substituted with one R3.

62. The compound of any one of claims 1-50 or 52, wherein R4and R4’together form an substituted 3- to 7-membered cycloalkyl that is substituted with one R3.

63. The compound of any one of the preceding claims, wherein D1is O.

64. The compound of any one of the preceding claims, wherein L is -L2-Y2-L3-, wherein: L2is a bond to Y2, -C(O)-, -C(O)NH-, -C(O)O-, -S(O)- or -SO2-; - 307 -4896-4398-0599.1120039.000146 | TYRA.037PCT Y2is a bond to L3, -(C1-12alk)-, -(C2-12alken)-, -(C2-12alkyn)-, -(C1-12heteroalk)-, -C1- 12alk-C(O)-, -C1-12alk-C(O)-NH-C1-12alk-C(O)-, -C(O)-C1-12alk-C(O)NH-, -NH- C2-12alkyn-, -O-(C0-12alk)-, -(C0-12alk)-O-, -O-(CH2CH2O)p-, -NH-(CH2CH2O)p-, - (CH2CH2O)p-, wherein p is 1-3, -optionally substituted cycloalk-, -optionally substituted heterocycloalk-, -optionally substituted aryl-, -optionally substituted heteroaryl-; and L3is a bond to Z2, -NH-, -O-, -(C1-12alk)-, -(C2-12alken)-, -(C2-12alkyn)-, -(C1-12heteroalk)-, -O-(C1-12alk)-C(O)-, -NH-(C1-12alk)-C(O)-, C(O)-(C1-12alk)-NH-, - C1-12alk-C(O)-NH-C1-12alk-C(O)-, -C(O)-NH-(C1-12alk)-, -O-(C1-12alk)-, -C(O)-O- (C1-12alk)-, -C(O)-(C1-12alk)-, -C1-12alk-C(O)-, -optionally substituted cycloalk-, - optionally substituted heterocycloalk-, -optionally substituted spiroheterocycloalky-, -optionally substituted aryl-, -optionally substituted heteroaryl-, -C(O)C1-12alk-(optionally substituted heterocycloalk)-, -C(O)-C1-12alk-C(O)NH-, -NH-C2-12alkyn-, -(C1-12alk)-O-, -O-(CH2CH2O)p-, -NH- (CH2CH2O)p-, -(CH2CH2O)p-, wherein p is 1-3.

65. The compound of any one of claims 1-63, wherein L is -L2-Y2-L3-, wherein: L2is a bond to Y2, -C(O)-, -C(O)NH-, -C(O)O-, -S(O)- or -SO2-; Y2is a bond to L3, -(C1-12alk)-, -(C2-12alken)-, -(C2-12alkyn)-, -(C1-12heteroalk)-, -C1- 12alk-C(O)-, -C1-12alk-C(O)-NH-C1-12alk-C(O)-, -C(O)-C1-12alk-C(O)NH-, -NH- C2-12alkyn-, -O-(C0-12alk)-, -(C0-12alk)-O-, -O-(CH2CH2O)p-, -NH-(CH2CH2O)p-, - (CH2CH2O)p-, wherein p is 1-3, -optionally substituted cycloalk-, -optionally substituted heterocycloalk-, -optionally substituted aryl-, -optionally substituted heteroaryl-, -(C1-6alk)-NH-, -(CH2CH2O)p-(C1-6alk)-, wherein p is 1-4, - (CH2CH2O)p-(C1-6alk)-NH-, wherein p is 1-4, -optionally substituted heterocycloalk-C(O)-(CH2CH2O)p-(C1-6alk)-, wherein p is 1-4, -(C1-6alk)- cycloalkyl-(C1-6alk)-NH, or -C1-12alk-(optionally substituted heterocycloalk)-; and L3is a bond to Z2, -NH-, -O-, -(C1-12alk)-, -(C2-12alken)-, -(C2-12alkyn)-, -(C1-12heteroalk)-, -O-(C1-12alk)-C(O)-, -NH-(C1-12alk)-C(O)-, C(O)-(C1-12alk)-NH-, - C1-12alk-C(O)-NH-C1-12alk-C(O)-, -C(O)-NH-(C1-12alk)-, -O-(C1-12alk)-, -C(O)-O- (C1-12alk)-, -C(O)-(C1-12alk)-, -C1-12alk-C(O)-, -optionally substituted cycloalk-, - optionally substituted heterocycloalk-, -optionally substituted spiroheterocycloalky-, -optionally substituted aryl-, -optionally substituted - 308 -4896-4398-0599.1120039.000146 | TYRA.037PCT heteroaryl-, -C(O)C1-12alk-(optionally substituted heterocycloalk)-, -C(O)-C1- 12alk-C(O)NH-, -NH-C2-12alkyn-, -(C1-12alk)-O-, -O-(CH2CH2O)p-, -NH- (CH2CH2O)p-, -(CH2CH2O)p-, wherein p is 1-3, -(C1-6alk)-C(O)- (optionally substituted heterocycloalk), -C(O)-(optionally substituted heterocycloalk)-, -C(O)- (CH2CH2O)p-(C1-6alk)-(optionally substituted heterocycloalk), wherein p is 1-4, - C(O)-(C1-12alk)-O-, -(C1-12alk)-C(O)-NH-, -C1-12alk-C(O)-(optionally substituted heterocycloalk)-, -C1-12alk-(optionally substituted heterocycloalk)-, or -C(O)- (CH2CH2O)p-(C1-6alk), wherein p is 1-4; or -(optionally substituted heterocycloalk)-.

66. The compound of claim 64 or claim 65, wherein L2is -C(O)-.

67. The compound of claim 64 or claim 65, wherein L2is -CONH-.

68. The compound of claim 64 or claim 65, wherein L2is -C(O)O-.

69. The compound of claim 64 or claim 65, wherein L2is -S(O)-.

70. The compound of claim 64 or claim 65, wherein L2is -SO2-.

71. The compound of any one of claims 64-70, wherein Y2is a bond to L3.

72. The compound of any one of claims 64-70, wherein Y2is -(C1-8alk)-.

73. The compound of any one of claims 64-70, wherein Y2is -(C1-8heteroalk)-.

74. The compound of any one of claims 64-70, wherein Y2is -C1-8alk-C(O)-.

75. The compound of any one of claims 64-70, wherein Y2is -C1-8alk-C(O)-NH-C1-8alk- C(O)-.

76. The compound of any one of claims 64-70, wherein Y2is -optionally substituted cycloalk-.

77. The compound of any one of claims 64-70, wherein Y2is -optionally substituted heterocycloalk-.

78. The compound of any one of claims 64-70, wherein Y2is optionally substituted aryl. - 309 -4896-4398-0599.1120039.000146 | TYRA.037PCT 79. The compound of any one of claims 64-70, wherein Y2is optionally substituted heteroaryl.

80. The compound of any one of claims 65-70, wherein Y2is -(C1-6alk)-NH-.

81. The compound of any one of claims 65-70, wherein Y2is -(CH2CH2O)p-(C1-6alk)-, wherein p is 1-4.

82. The compound of any one of claims 65-70, wherein Y2is -(CH2CH2O)p-(C1-6alk)-NH-, wherein p is 1-4.

83. The compound of any one of claims 65-70, wherein Y2is -optionally substituted heterocycloalk-C(O)-(CH2CH2O)p-(C1-6alk)-, wherein p is 1-4.

84. The compound of any one of claims 65-70, wherein Y2is -(C1-6alk)-cycloalkyl-(C1-6alk)- NH-.

85. The compound of any one of claims 65-70, wherein Y2is -C1-12alk-(optionally substituted heterocycloalk)-.

86. The compound of any one of claims 64-70 or 72-85, wherein L3is a bond to Z2.

87. The compound of any one of claims 64-85, wherein L3is -NH-.

88. The compound of any one of claims 64-85, wherein L3is -C(O)-(C1-8alk)-NH-.

89. The compound of any one of claims 64-85, wherein L3is -C(O)-NH-(C1-8alk)-.

90. The compound of any one of claims 64-85, wherein L3is -O-(C1-8alk)-.

91. The compound of any one of claims 64-85, wherein L3is -C(O)-O-(C1-6alk)-.

92. The compound of any one of claims 64-85, wherein L3is -C(O)-(C1-6alk)-.

93. The compound of any one of claims 64-85, wherein L3is optionally substituted heterocycloalk-.

94. The compound of any one of claims 64-85, wherein L3is optionally substituted spiroheterocycloalkyl. - 310 -4896-4398-0599.1120039.000146 | TYRA.037PCT 95. The compound of any one of claims 64-85, wherein L3is optionally substituted aryl.

96. The compound of any one of claims 64-85, wherein L3is optionally substituted heteroaryl.

97. The compound of any one of claims 64-85, wherein L3is -C(O)C1-6alk-(optionally substituted heterocycloalkyl.

98. The compound of any one of claims 64-85, wherein L3is -C(O)-C1-6alk-C(O)NH-.

99. The compound of any one of claims 64-85, wherein L3is -NH-C2-6alkyn-.

100. The compound of any one of claims 64-85, wherein L3is -O-(C1-6alk)-.

101. The compound of any one of claims 64-85, wherein L3is -(C1-6alk)-O-.

102. The compound of any one of claims 64-85, wherein L3is -O-(CH2CH2O)p-.

103. The compound of any one of claims 64-85, wherein L3is -NH-(CH2CH2O)p-, 104. The compound of any one of claims 64-85, wherein L3is -(CH2CH2O)p-.

105. The compound of any one of claims 65-85, wherein L3is -(C1-6alk)-C(O)- hetreocycloalky.

106. The compound of any one of claims 65-85, wherein L3is -C(O)-(optionally substituted heterocycloalk)-.

107. The compound of any one of claims 65-85, wherein L3is -C(O)-(CH2CH2O)p-(C1- 6alk)-(optionally substituted heterocycloalk) wherein p is 1-4.

108. The compound of any one of claims 65-85, wherein L3is -C(O)-(C1-12alk)-O-.

109. The compound of any one of claims 65-85, wherein L3is -(C1-12alk)-C(O)-NH-.

110. The compound of any one of claims 65-85, wherein L3is -C1-12alk-C(O)-(optionally substituted heterocycloalk)-. - 311 -4896-4398-0599.1120039.000146 | TYRA.037PCT 111. The compound of any one of claims 65-85, wherein L3is -C1-12alk-(optionally substituted heterocycloalk)-.

112. The compound of any one of claims 65-85, wherein L3is -C(O)-(CH2CH2O)p-(C1- 6alk)-(optionally substituted heterocycloalk)- wherein p is 1-4.

113. The compound of claim 1, that is any one of formula II-VIII, wherein each Q1is, independently, N or CRC, wherein RCis H or C1-6alkyl, provided that at least one Q1is N:- 312 -4896-4398-0599.1120039.000146 | TYRA.037PCTpharmaceutically acceptable salt thereof. 114.- 313 -4896-4398-0599.11200399..0000114466 || TYRRAA.0.03377PPCCTT14 - 4896- -43988--0559999..1 -314-1200399..0000114466 || TYRRAA.0.03377PPCCTTLO}-31155- - 4896- -43988--0559999..11200399..0000114466 || TYRRAA.0.03377PPCCTT- 316- - 4896- -43988--0559999..11200399..0000114466 || TYRRAA.0.03377PPCCTTg §-31177- - 4896- -43988--0559999..11200399..0000114466 || TYRRAA.0.03377PPCCTTS- 318 - 4896- -43988--0559999..11200399..0000114466 || TYRRAA.0.03377PPCCTT- 319 - 4896- -43988--0559999..11200399..0000114466 || TYRRAA.0.03377PPCCTTM P- 320 - 4896- -43988--0559999..11200399..0000114466 || TYRRAA.0.03377PPCCTT- 321 - - 4896- -43988--0559999..11200399..0000114466 || TYRRAA.0.03377PPCCTT- 3222 - 4896- -43988--0559999..1120039.000146 | TYRA.037PCT115. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is: 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-[4-[1-[2- (2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperidine-4-carbonyl]piperazin-1- yl]pyridine-3-carbonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-[4-[1-[2- (2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]piperidine-4-carbonyl]piperazin-1- yl]pyridine-3-carbonitrile; 4-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6- diazaspiro[3.3]heptane-2-carbonyl]-1-piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3- dione; 5-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-3-fluoro-2- pyridyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-1-piperidyl]-2-(2,6-dioxo-3- piperidyl)isoindoline-1,3-dione; 5-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6- diazaspiro[3.3]heptane-2-carbonyl]-1-piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3- dione; 4-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-3-fluoro-2- pyridyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-1-piperidyl]-2-(2,6-dioxo-3- piperidyl)isoindoline-1,3-dione; 4-[4-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6- diazaspiro[3.3]-heptan-2-yl]sulfonyl]-1-piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline- 1,3-dione; - 323 -4896-4398-0599.1120039.000146 | TYRA.037PCT 4-[4-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6- diazaspiro[3.3]heptan-2-yl]sulfonyl]-1-piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline- 1,3-dione; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-[4-[1-[2-[[2- (2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]acetyl]piperidine-4- carbonyl]piperazin-1-yl]pyridine-3-carbonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-[4-[1-[2-[[2- (2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]acetyl]piperidine-4- carbonyl]piperazin-1-yl]pyridine-3-carbonitrile; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-[4-[1-[4-[[2- (2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]butanoyl]piperidine-4- carbonyl]piperazin-1-yl]pyridine-3-carbonitrile; 4-[[4-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,6-diazaspiro[3.3]heptane-2-carbonyl]-1-piperidyl]-4-oxo-butyl]amino]-2-(2,6-dioxo-3- piperidyl)isoindoline-1,3-dione; 5-[[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,6-diazaspiro[3.3]heptane-2-carbonyl]-1-piperidyl]-2-oxo-ethyl]amino]-2-(2,6-dioxo-3- piperidyl)isoindoline-1,3-dione; 4-[[4-[4-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,6-diazaspiro[3.3]heptan-2-yl]sulfonyl]-1-piperidyl]-4-oxo-butyl]amino]-2-(2,6-dioxo-3- piperidyl)isoindoline-1,3-dione; 4-[[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,6-diazaspiro[3.3]-heptane-2-carbonyl]-1-piperidyl]-2-oxo-ethyl]amino]-2-(2,6-dioxo-3- piperidyl)-isoindoline-1,3-dione; 4-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6- diazaspiro[3.3]-heptane-2-carbonyl]-piperazin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline- 1,3-dione; 5-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6- diazaspiro[3.3]-heptane-2-carbonyl]-piperazin-1-yl]-2-(2,6-dioxo-3-piperidyl)- isoindoline-1,3-dione; - 324 -4896-4398-0599.1120039.000146 | TYRA.037PCT 5-[[4-[4-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,6-diazaspiro[3.3]-heptan-2-yl]sulfonyl]-1-piperidyl]-4-oxo-butyl]amino]-2-(2,6-dioxo- 3-piperidyl)-isoindoline-1,3-dione; 4-[4-[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,6-diazaspiro[3.3]-heptane-2-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4-hydroxy-1- piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione; 5-[[2-[4-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,6-diazaspiro[3.3]-heptan-2-yl]sulfonyl]-1-piperidyl]-2-oxo-ethyl]amino]-2-(2,6-dioxo- 3-piperidyl)isoindoline-1,3-dione; 5-[4-[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,6-diazaspiro[3.3]-heptane-2-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4-hydroxy-1- piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione; 2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]ethyl 4-[6-[5-[5-[(1R)-1-(3,5- dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]-heptane-2- carbonyl]piperidine-1-carboxylate; 3-[4-[4-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,6-diazaspiro[3.3]-heptan-2-yl]sulfonyl]-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1- yl]piperidine-2,6-dione; 5-[[4-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,6-diazaspiro[3.3]-heptane-2-carbonyl]-1-piperidyl]-4-oxo-butyl]amino]-2-(2,6-dioxo-3- piperidyl)isoindoline-1,3-dione; 3-[4-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6- diazaspiro[3.3]-heptane-2-carbonyl]-1-piperidyl]-3-methyl-2-oxo-benzimidazol-1- yl]piperidine-2,6-dione; 3-[6-[1-[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]-heptane-2-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]- 1-methyl-indazol-3-yl]piperidine-2,6-dione; 3-[4-[1-[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]-heptane-2-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]- 3-fluoro-anilino]piperidine-2,6-dione; - 325 -4896-4398-0599.1120039.000146 | TYRA.037PCT 2-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]ethyl 6-[5-[5-[(1R)-1- (3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]-heptane- 2-carboxylate; 3-[6-[4-[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]-heptane-2-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4-hydroxy-1- piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-[4-[1-[2-[1- [2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-4-hydroxy-4-piperidyl]- acetyl]piperidine-4-carbonyl]piperazin-1-yl]pyridine-3-carbonitrile; 1-[6-[4-[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]-heptane-2-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4-hydroxy-1- piperidyl]-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione; 1-[6-[1-[2-[4-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]-heptan-2-yl]sulfonyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]- 1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione; 4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6- diazaspiro[3.3]-heptane-2-carbonyl]-N-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo- isoindolin-4-yl]ethyl]piperidine-1-carboxamide; 6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-N-[3-[2- (2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]prop-2-ynyl]-2,6- diazaspiro[3.3]heptane-2-carboxamide; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-[2-[[1-[2- [[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]acetyl]-4- piperidyl]sulfonyl]-2,6-diazaspiro[3.3]heptan-6-yl]pyridine-3-carbonitrile; N-[1-[3-cyano-5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3- yl]-2-pyridyl]-3-methyl-azetidin-3-yl]-1-[2-[1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo- isoindolin-5-yl]-4-hydroxy-4-piperidyl]acetyl]piperidine-4-carboxamide; 1-[6-[1-[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]-heptane-2-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]- 1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione; - 326 -4896-4398-0599.1120039.000146 | TYRA.037PCT 5-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3- dione; 5-[4-[2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2- azaspiro[3.3]heptane-6-carbonyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline- 1,3-dione; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-[2-[1-[2-[[2- (2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]acetyl]piperidine-4-carbonyl]- 2,6-diazaspiro[3.3]heptan-6-yl]pyridine-3-carbonitrile; 3-[4-[[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,6-diazaspiro[3.3]-heptane-2-carbonyl]-1-piperidyl]-2-oxo-ethyl]amino]-1-oxo- isoindolin-2-yl]piperidine-2,6-dione; 5-[4-[1-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperidine-4-carbonyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3- dione; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-[2-[1-[2-[1- [2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-4-hydroxy-4- piperidyl]acetyl]piperidine-4-carbonyl]-2,6-diazaspiro[3.3]-heptan-6-yl]pyridine-3- carbonitrile; 5-[[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-2-oxo-ethyl]amino]-2-(2,6-dioxo-3- piperidyl)isoindoline-1,3-dione; 5-[[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazin-1-yl]sulfonyl-1-piperidyl]-2-oxo-ethyl]amino]-2-(2,6-dioxo-3- piperidyl)-isoindoline-1,3-dione; 1-[6-[4-[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4-hydroxy-1-piperidyl]-1- methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione; - 327 -4896-4398-0599.1120039.000146 | TYRA.037PCT 1-[6-[4-[2-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,6-diazaspiro[3.3]heptan-2-yl]-2-oxo-ethyl]-4-hydroxy-1-piperidyl]-1-methyl-indazol-3- yl]hexahydropyrimidine-2,4-dione; 5-[4-[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4-hydroxy-1-piperidyl]-2-(2,6- dioxo-3-piperidyl)isoindoline-1,3-dione; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-[4-[1-[2-[[2- (2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]amino]acetyl]piperidine-4- carbonyl]piperazin-1-yl]pyridine-3-carbonitrile; 3-[5-[[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,6-diazaspiro[3.3]heptane-2-carbonyl]-1-piperidyl]-2-oxo-ethyl]amino]-1-oxo- isoindolin-2-yl]piperidine-2,6-dione; N-[1-[3-cyano-5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3- yl]-2-pyridyl]-3-methyl-azetidin-3-yl]-1-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo- isoindolin-5-yl]amino]acetyl]piperidine-4-carboxamide; 5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3-yl]-2-[4-[1-[2-[[2- (2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]acetyl]piperidine-4- carbonyl]piperazin-1-yl]pyridine-3-carbonitrile; 5-[3-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6- diazaspiro[3.3]heptan-2-yl]sulfonyl]propylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline- 1,3-dione; 4-[3-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6- diazaspiro[3.3]heptan-2-yl]sulfonyl]propylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline- 1,3-dione; 1-[6-[1-[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]-1-methyl-indazol- 3-yl]hexahydropyrimidine-2,4-dione; 1-[6-[[2-[4-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]heptan-2-yl]sulfonyl]-1-piperidyl]-2-oxo-ethyl]amino]-1- methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione; - 328 -4896-4398-0599.1120039.000146 | TYRA.037PCT N-[1-[3-cyano-5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3- yl]-2-pyridyl]-3-methyl-azetidin-3-yl]-1-[2-[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl- indazol-6-yl]-1-piperidyl]acetyl]-piperidine-4-carboxamide; N-[1-[3-cyano-5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3- yl]-2-pyridyl]-3-methyl-azetidin-3-yl]-1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]-2- fluoro-phenyl]-1-piperidyl]acetyl]piperidine-4-carboxamide; 5-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6- diazaspiro[3.3]heptan-2-yl]-N-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-5- oxo-pentanamide; 5-[4-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6- diazaspiro[3.3]heptan-2-yl]sulfonyl]-1-piperidyl]-N-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo- isoindolin-5-yl]-5-oxo-pentanamide; 4-[3-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6- diazaspiro[3.3]heptan-2-yl]sulfonyl]propoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3- dione; 5-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazin-1-yl]sulfonyl-1-piperidyl]-N-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo- isoindolin-5-yl]-5-oxo-pentanamide; 1-[6-[1-[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazin-1-yl]sulfonyl-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]-1-methyl-indazol- 3-yl]hexahydropyrimidine-2,4-dione; N-[1-[3-cyano-5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-6-methoxy-1H-indazol-3- yl]-2-pyridyl]-3-methyl-azetidin-3-yl]-1-[2-[4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1- methyl-indazol-6-yl]-1-piperidyl]acetyl]piperidine-4-carboxamide; 5-[3-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6- diazaspiro[3.3]heptan-2-yl]sulfonyl]propoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3- dione; 6-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6- diazaspiro[3.3]heptan-2-yl]-N-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-6- oxo-hexanamide; - 329 -4896-4398-0599.1120039.000146 | TYRA.037PCT N-[2-[2-[3-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,6-diazaspiro[3.3]heptan-2-yl]-3-oxo-propoxy]ethoxy]ethyl]-2-[[2-(2,6-dioxo-3- piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]acetamide; N-[2-[2-[3-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,6-diazaspiro[3.3]heptan-2-yl]-3-oxo-propoxy]ethoxy]ethyl]-2-[2-(2,6-dioxo-3- piperidyl)-1,3-dioxo-isoindolin-5-yl]oxy-acetamide; N-[2-[2-[3-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,6-diazaspiro[3.3]heptan-2-yl]-3-oxo-propoxy]ethoxy]ethyl]-2-[2-(2,6-dioxo-3- piperidyl)-1,3-dioxo-isoindolin-4-yl]oxy-acetamide; 6-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6- diazaspiro[3.3]heptan-2-yl]-N-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]-6- oxo-hexanamide; 5-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6- diazaspiro[3.3]heptan-2-yl]-N-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]-5- oxo-pentanamide; 5-[4-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6- diazaspiro[3.3]heptan-2-yl]sulfonyl]-1-piperidyl]-N-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo- isoindolin-4-yl]-5-oxo-pentanamide; 5-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazin-1-yl]sulfonyl-1-piperidyl]-N-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo- isoindolin-4-yl]-5-oxo-pentanamide; N-[2-[2-[3-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,6-diazaspiro[3.3]heptan-2-yl]-3-oxo-propoxy]ethoxy]ethyl]-2-[[2-(2,6-dioxo-3- piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]acetamide; 1-[6-[1-[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]-5- fluoro-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione; 1-[6-[1-[2-[4-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]heptan-2-yl]sulfonyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]- 5-fluoro-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione; - 330 -4896-4398-0599.1120039.000146 | TYRA.037PCT 1-[6-[4-[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-1-piperidyl]-2-oxo-ethyl]-1-piperidyl]-1- methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione; 1-[6-[4-[2-[4-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]heptan-2-yl]sulfonyl]-1-piperidyl]-2-oxo-ethyl]-1-piperidyl]- 1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione; 5-[2-[2-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,6-diazaspiro[3.3]heptan-2-yl]sulfonyl]ethoxy]ethoxy]-2-(2,6-dioxo-3- piperidyl)isoindoline-1,3-dione; 1-[6-[4-[2-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazin-1-yl]-2-oxo-ethyl]piperazin-1-yl]-5-fluoro-1-methyl-indazol-3- yl]hexahydropyrimidine-2,4-dione; 1-[6-[4-[2-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazin-1-yl]-2-oxo-ethyl]-1-piperidyl]-5-fluoro-1-methyl-indazol-3- yl]hexahydropyrimidine-2,4-dione; 1-[6-[4-[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-1-piperidyl]-2-oxo-ethyl]piperazin-1-yl]- 1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione; 3-[4-[1-[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]-3-fluoro- anilino]piperidine-2,6-dione; 1-[6-[1-[2-[4-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]heptan-2-yl]sulfonyl]-1-piperidyl]acetyl]-4-piperidyl]-1- methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione; 1-[6-[1-[6-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,6-diazaspiro[3.3]heptan-2-yl]-6-oxo-hexanoyl]-4-piperidyl]-1-methyl-indazol-3- yl]hexahydropyrimidine-2,4-dione; N-[2-[2-[2-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]heptan-2-yl]sulfonyl]ethoxy]ethoxy]ethyl]-2-[[2-(2,6-dioxo- 3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]acetamide; - 331 -4896-4398-0599.1120039.000146 | TYRA.037PCT 4-[2-[2-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,6-diazaspiro[3.3]heptan-2-yl]sulfonyl]ethoxy]ethoxy]-2-(2,6-dioxo-3- piperidyl)isoindoline-1,3-dione; 4-[2-[2-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,6-diazaspiro[3.3]heptan-2-yl]sulfonyl]ethoxy]ethoxy]-2-(2,6-dioxo-3- piperidyl)isoindoline-1,3-dione; 4-[2-[2-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,6-diazaspiro[3.3]heptan-2-yl]sulfonyl]ethoxy]ethoxy]-2-(2,6-dioxo-3- piperidyl)isoindoline-1,3-dione; 4-[2-[2-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,6-diazaspiro[3.3]heptan-2-yl]sulfonyl]ethoxy]ethoxy]-2-(2,6-dioxo-3- piperidyl)isoindoline-1,3-dione; 1-[4-[1-[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]-3-fluoro- phenyl]hexahydropyrimidine-2,4-dione; 2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-N-[2-(2,6-dioxo-3-piperidyl)-1-oxo- isoindolin-4-yl]acetamide; 1-[6-[1-[3-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]propanoyl]-4-piperidyl]-1-methyl-indazol-3- yl]hexahydropyrimidine-2,4-dione; 3-[4-[[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-2-oxo-ethyl]amino]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione; 1-[6-[1-[2-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]-5-fluoro-1-methyl-indazol-3- yl]hexahydropyrimidine-2,4-dione; 1-[6-[1-[7-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,6-diazaspiro[3.3]heptan-2-yl]-7-oxo-heptanoyl]-4-piperidyl]-1-methyl-indazol-3- yl]hexahydropyrimidine-2,4-dione; - 332 -4896-4398-0599.1120039.000146 | TYRA.037PCT N-[2-[2-[3-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]heptan-2-yl]sulfonyl]propoxy]ethoxy]ethyl]-2-; [[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]acetamide; 1-[6-[1-[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]acetyl]-4-piperidyl]-1-methyl-indazol-3- yl]hexahydropyrimidine-2,4-dione; N-[2-[2-[2-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]heptan-2-yl]sulfonyl]ethoxy]-ethoxy]ethyl]-2-[2-(2,6-dioxo- 3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxy-acetamide; N-[2-[2-[2-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]heptan-2-yl]sulfonyl]ethoxy]ethoxy]ethyl]-2-[[2-(2,6-dioxo- 3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]acetamide; N-[2-[2-[2-[[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]heptan-2-yl]sulfonyl]-ethoxy]ethoxy]ethyl]-2-[2-(2,6-dioxo- 3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxy-acetamide; 1-[6-[1-[2-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazin-1-yl]acetyl]-4-piperidyl]-5-fluoro-1-methyl-indazol-3- yl]hexahydropyrimidine-2,4-dione; 2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-N-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1- methyl-indazol-6-yl]acetamide; N-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazin-1-yl]-2,2-dimethyl-4-oxo-butyl]-2-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-1-piperidyl]acetamide; 1-[6-[1-[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]acetyl]-4-piperidyl]-7-fluoro-1-methyl- indazol-3-yl]hexahydropyrimidine-2,4-dione; - 333 -4896-4398-0599.1120039.000146 | TYRA.037PCT 3-[5-[[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-2-oxo-ethyl]amino]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione; 1-[6-[1-[8-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,6-diazaspiro[3.3]heptan-2-yl]-8-oxo-octanoyl]-4-piperidyl]-1-methyl-indazol-3- yl]hexahydropyrimidine-2,4-dione; 1-[6-[1-[3-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-3-oxo-propyl]-4-piperidyl]-1-methyl-indazol- 3-yl]hexahydropyrimidine-2,4-dione; 1-[6-[1-[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]-7-fluoro-1-methyl- indazol-3-yl]hexahydropyrimidine-2,4-dione; 3-[4-[4-[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-2-oxo-ethyl]piperazin-1- yl]phenyl]piperidine-2,6-dione; N-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazin-1-yl]-2,2-dimethyl-4-oxo-butyl]-2-[4-[4-(2,6-dioxo-3- piperidyl)phenyl]piperazin-1-yl]acetamide; N-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazin-1-yl]-2,2-dimethyl-4-oxo-butyl]-2-[[2-(2,6-dioxo-3-piperidyl)-1,3- dioxo-isoindolin-5-yl]amino]acetamide; 1-[6-[1-[3-[3-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]heptan-2-yl]-3-oxo-propoxy]propanoyl]-4-piperidyl]-1- methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione; 5-[4-[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-2-oxo-ethyl]-1-piperidyl]-2-(2,6-dioxo-3- piperidyl)isoindoline-1,3-dione; N-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,6- diazaspiro[3.3]heptan-2-yl]-2,2-dimethyl-4-oxo-butyl]-2-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-1-piperidyl]acetamide; - 334 -4896-4398-0599.1120039.000146 | TYRA.037PCT 5-[1-[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]-2-(2,6-dioxo-3- piperidyl)isoindoline-1,3-dione; N-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazin-1-yl]-2,2-dimethyl-4-oxo-butyl]-2-[[2-(2,6-dioxo-3-piperidyl)-1-oxo- isoindolin-5-yl]amino]acetamide; N-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazin-1-yl]-2,2-dimethyl-4-oxo-butyl]-2-[4-[2-(2,6-dioxo-3-piperidyl)-1,3- dioxo-isoindolin-5-yl]-1-piperidyl]acetamide; N-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazin-1-yl]-2,2-dimethyl-4-oxo-butyl]-2-[1-[2-(2,6-dioxo-3-piperidyl)-1,3- dioxo-isoindolin-5-yl]-4-piperidyl]acetamide; 1-[6-[1-[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-1-piperidyl]acetyl]-4-piperidyl]-1- methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione; N-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazin-1-yl]-2,2-dimethyl-4-oxo-butyl]-2-[[2-(2,6-dioxo-3-piperidyl)-1,3- dioxo-isoindolin-4-yl]amino]acetamide; 5-[1-[2-[4-[2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,7-diazaspiro[3.4]octane-7-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]-2-(2,6- dioxo-3-piperidyl)isoindoline-1,3-dione; 5-[4-[2-[4-[2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,7-diazaspiro[3.4]octane-7-carbonyl]-1-piperidyl]-2-oxo-ethyl]-1-piperidyl]-2-(2,6- dioxo-3-piperidyl)isoindoline-1,3-dione; 5-[1-[3-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-3-oxo-propyl]-4-piperidyl]-2-(2,6-dioxo-3- piperidyl)isoindoline-1,3-dione; 1-[6-[1-[3-[4-[2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,7-diazaspiro[3.4]octane-7-carbonyl]-1-piperidyl]-3-oxo-propyl]-4-piperidyl]-1- methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione; - 335 -4896-4398-0599.1120039.000146 | TYRA.037PCT 3-[4-[4-[[1-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-4-piperidyl]methyl]piperazin-1-yl]phenyl]piperidine-2,6- dione; 5-[1-[4-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-4-oxo-butyl]-4-piperidyl]-2-(2,6-dioxo-3- piperidyl)isoindoline-1,3-dione; 5-[[2-[4-[2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,7-diazaspiro[3.4]octane-7-carbonyl]-1-piperidyl]-2-oxo-ethyl]amino]-2-(2,6-dioxo-3- piperidyl)isoindoline-1,3-dione; 1-[4-[4-[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-2-oxo-ethyl]piperazin-1- yl]phenyl]hexahydropyrimidine-2,4-dione; N-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazin-1-yl]-2,2-dimethyl-4-oxo-butyl]-2-[4-[4-(2,4- dioxohexahydropyrimidin-1-yl)phenyl]piperazin-1-yl]acetamide; N-[4-[2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,7- diazaspiro[3.4]octan-7-yl]-2,2-dimethyl-4-oxo-butyl]-2-[[2-(2,6-dioxo-3-piperidyl)-1,3- dioxo-isoindolin-5-yl]amino]acetamide; 1-[4-[4-[[1-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-4-piperidyl]methyl]piperazin-1- yl]phenyl]hexahydropyrimidine-2,4-dione; 5-[[2-[4-[2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,7-diazaspiro[3.5]nonane-7-carbonyl]-1-piperidyl]-2-oxo-ethyl]amino]-2-(2,6-dioxo-3- piperidyl)isoindoline-1,3-dione; 1-[6-[1-[3-[4-[2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,7-diazaspiro[3.5]nonane-7-carbonyl]-1-piperidyl]-3-oxo-propyl]-4-piperidyl]- 1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione; N-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazin-1-yl]-2,2-dimethyl-4-oxo-butyl]-2-[4-[4-[(2,6-dioxo-3- piperidyl)amino]-2-fluoro-phenyl]-1-piperidyl]acetamide; - 336 -4896-4398-0599.1120039.000146 | TYRA.037PCT 3-[4-[4-[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-2-oxo-ethyl]piperazin-1- yl]anilino]piperidine-2,6-dione; 3-[4-[1-[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazin-1-yl]sulfonyl-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]anilino]piperidine- 2,6-dione; 3-[4-[4-[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazin-1-yl]sulfonyl-1-piperidyl]-2-oxo-ethyl]piperazin-1- yl]anilino]piperidine-2,6-dione; 3-[4-[1-[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]anilino]piperidine- 2,6-dione; 3-[4-[1-[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]-3-methoxy- anilino]piperidine-2,6-dione; 3-[4-[1-[2-[2-[2-[3-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]- 2-pyridyl]piperazine-1-carbonyl]-1-piperidyl]-3-oxo-propoxy]ethoxy]ethoxy]ethyl]-4- piperidyl]-3-fluoro-anilino]piperidine-2,6-dione; 3-[4-[1-[2-[2-[2-[2-[3-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3- yl]-2-pyridyl]piperazine-1-carbonyl]-1-piperidyl]-3-oxo- propoxy]ethoxy]ethoxy]ethoxy]ethyl]-4-piperidyl]-3-fluoro-anilino]piperidine-2,6-dione; 1-[6-[1-[2-[3-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-3-oxo-propoxy]ethyl]-4-piperidyl]-1-methyl- indazol-3-yl]hexahydropyrimidine-2,4-dione; 3-[4-[1-[2-[3-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-3-oxo-propoxy]ethyl]-4-piperidyl]-3-fluoro- anilino]piperidine-2,6-dione; 1-[6-[1-[2-[2-[3-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-3-oxo-propoxy]ethoxy]ethyl]-4-piperidyl]-1- methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione; - 337 -4896-4398-0599.1120039.000146 | TYRA.037PCT 5-[1-[2-[2-[2-[2-[3-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]- 2-pyridyl]piperazine-1-carbonyl]-1-piperidyl]-3-oxo- propoxy]ethoxy]ethoxy]ethoxy]ethyl]-4-piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline- 1,3-dione; 5-[1-[2-[2-[2-[3-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-3-oxo-propoxy]ethoxy]ethoxy]ethyl]-4- piperidyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione; 1-[4-[4-[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazin-1-yl]sulfonyl-1-piperidyl]-2-oxo-ethyl]piperazin-1- yl]phenyl]hexahydropyrimidine-2,4-dione; 1-[4-[4-[2-[4-[6-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-1-piperidyl]-2-oxo-ethyl]piperazin-1- yl]phenyl]hexahydropyrimidine-2,4-dione; N-[4-[2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,7- diazaspiro[3.4]octan-7-yl]-2,2-dimethyl-4-oxo-butyl]-2-[4-(2,4- dioxohexahydropyrimidin-1-yl)anilino]acetamide; 3-[4-[1-[2-[2-[3-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-3-oxo-propoxy]ethoxy]ethyl]-4-piperidyl]-3- fluoro-anilino]piperidine-2,6-dione; 1-[4-[4-[2-[4-[2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,7-diazaspiro[3.5]nonane-7-carbonyl]-1-piperidyl]-2-oxo-ethyl]piperazin-1- yl]phenyl]hexahydropyrimidine-2,4-dione; 1-[4-[4-[2-[4-[2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,7-diazaspiro[3.4]octane-7-carbonyl]-1-piperidyl]-2-oxo-ethyl]piperazin-1- yl]phenyl]hexahydropyrimidine-2,4-dione; 1-[4-[1-[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazin-1-yl]sulfonyl-1-piperidyl]-2-oxo-ethyl]-4- piperidyl]phenyl]hexahydropyrimidine-2,4-dione; - 338 -4896-4398-0599.1120039.000146 | TYRA.037PCT 5-[1-[2-[2-[3-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-3-oxo-propoxy]ethoxy]ethyl]-4-piperidyl]-2- (2,6-dioxo-3-piperidyl)isoindoline-1,3-dione; 1-[4-[1-[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4- piperidyl]phenyl]hexahydropyrimidine-2,4-dione; 1-[6-[1-[2-[2-[2-[3-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]- 2-pyridyl]piperazine-1-carbonyl]-1-piperidyl]-3-oxo-propoxy]ethoxy]ethoxy]ethyl]-4- piperidyl]-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione; N-[4-[2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,8- diazaspiro[3.5]nonan-8-yl]-2,2-dimethyl-4-oxo-butyl]-2-[4-(2,4- dioxohexahydropyrimidin-1-yl)anilino]acetamide; 1-[4-[4-[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-2-oxo-ethyl]piperazin-1-yl]-3-fluoro- phenyl]hexahydropyrimidine-2,4-dione; 1-[4-[4-[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazin-1-yl]sulfonyl-1-piperidyl]-2-oxo-ethyl]piperazin-1-yl]-3-fluoro- phenyl]hexahydropyrimidine-2,4-dione; 1-[4-[4-[3-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-3-oxo-propyl]piperazin-1- yl]phenyl]hexahydropyrimidine-2,4-dione; N-[4-[2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,7- diazaspiro[3.4]octan-7-yl]-2,2-dimethyl-4-oxo-butyl]-3-[[2-(2,6-dioxo-3-piperidyl)-1,3- dioxo-isoindolin-5-yl]amino]propanamide; N-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazin-1-yl]-2,2-dimethyl-4-oxo-butyl]-3-[4-[4-(2,4- dioxohexahydropyrimidin-1-yl)phenyl]piperazin-1-yl]propanamide; 1-[4-[4-[2-[4-[2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,8-diazaspiro[3.5]nonane-8-carbonyl]-1-piperidyl]-2-oxo-ethyl]piperazin-1- yl]phenyl]hexahydropyrimidine-2,4-dione; - 339 -4896-4398-0599.1120039.000146 | TYRA.037PCT N-[4-[2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-2,7- diazaspiro[3.4]octan-7-yl]-2,2-dimethyl-4-oxo-butyl]-3-[4-[4-(2,4- dioxohexahydropyrimidin-1-yl)phenyl]piperazin-1-yl]propanamide; 1-[4-[4-[3-[4-[2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]-2,7-diazaspiro[3.4]octane-7-carbonyl]-1-piperidyl]-3-oxo-propyl]piperazin-1- yl]phenyl]hexahydropyrimidine-2,4-dione; 1-[4-[4-[2-[2-[3-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-3-oxo-propoxy]ethoxy]-ethyl]piperazin-1- yl]phenyl]hexahydropyrimidine-2,4-dione; N-[[1-[2-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazin-1-yl]-2-oxo-ethyl]cyclopropyl]methyl]-2-[4-[4-(2,4- dioxohexahydropyrimidin-1-yl)phenyl]piperazin-1-yl]acetamide; 1-[4-[4-[[1-[2-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]- 2,7-diazaspiro[3.5]nonane-7-carbonyl]-4-piperidyl]methyl]piperazin-1- yl]phenyl]hexahydropyrimidine-2,4-dione; 1-[4-[4-[2-[2-[3-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazin-1-yl]-3-oxo-propoxy]ethoxy]ethyl]piperazin-1- yl]phenyl]hexahydropyrimidine-2,4-dione; 1-[4-[4-[[1-[2-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazin-1-yl]-2-oxo-ethyl]-4-piperidyl]methyl]piperazin-1- yl]phenyl]hexahydropyrimidine-2,4-dione; 1-[4-[4-[2-[4-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazine-1-carbonyl]-1-piperidyl]-2-oxo-ethyl]-4-hydroxy-1- piperidyl]phenyl]hexahydropyrimidine-2,4-dione; or N-[[1-[2-[4-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2- pyridyl]piperazin-1-yl]-2-oxo-ethyl]-cyclopropyl]methyl]-3-[4-[4-(2,4- dioxohexahydropyrimidin-1-yl) Phenyl-piperazin-1-yl]propanamide.

116. A compound, or a pharmaceutical salt thereof, wherein the compound is: - 340 -4896-4398-0599.1120039.000146 | TYRA.037PCT N-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-1-[2-[1-[2- (2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]acetyl]-piperidine-4- carboxamide; N-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-1-[2-[4-[2- (2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-1-piperidyl]acetyl]-piperidine-4- carboxamide; N-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-4-[[2-[4-[2- (2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-1-piperidyl]acetyl]amino]-3,3- dimethyl-butanamide; or N-[5-[5-[(1R)-1-(3,5-dichloro-4-pyridyl)ethoxy]-1H-indazol-3-yl]-2-pyridyl]-4-[[2-[1-[2- (2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]acetyl]amino]-3,3- dimethyl-butanamide.

117. A pharmaceutical composition comprising a compound of any one of claims 1-116, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

118. A method of treating cancer in a subject in need thereof comprising administering to the subject the compound of any one of claims 1-116 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 117.

119. The method of claim 118, wherein the cancer is urothelial carcinoma, breast carcinoma, endometrial adenocarcinoma, ovarian carcinoma, primary glioma, cholangiocarcinoma, gastric adenocarcinoma, non-small cell lung carcinoma, pancreatic exocrine carcinoma, oral cancer, prostate cancer, bladder cancer, colorectal carcinoma, renal cell carcinoma, neuroendocrine carcinoma, myeloproliferative neoplasm, head and neck (squamous) cancer, melanoma, leiomyosarcoma, or sarcoma, or a combination thereof.

120. The method of claim 119, wherein the cancer is an intrahepatic cholangiocarcinoma. - 341 -4896-4398-0599.1120039.000146 | TYRA.037PCT 121. The method of any one of claims 118-120, wherein the cancer is an FGFR-mutant cancer.

122. The method of any one of claims 118-120, wherein the cancer is an FGFR3-mutant cancer. - 342 -4896-4398-0599.1

Images