WO2021155006A1

WO2021155006A1 - Inhibitors of cyclin-dependent kinases and uses thereof

Info

Publication number: WO2021155006A1
Application number: PCT/US2021/015505
Authority: WO
Inventors: Zenon D. Konteatis; Mingzong Li; Zhihua Sui
Original assignee: Les Laboratoires Servier Sas; Servier Pharmaceuticals, Llc
Priority date: 2020-01-31
Filing date: 2021-01-28
Publication date: 2021-08-05

Abstract

Provided are novel compounds of Formula (I); pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful in the treatment of diseases and disorders mediated by CDK such as cancer.

Description

INHIBITORS OF CY CUIN-DEPENDENT KINASES AND USES THEREOF

REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the filing date of U.S. Provisional Patent Application No. 62/968,949, filed on January 31, 2020, the entire contents of which are incorporated herein by reference.

BACKGROUND

Cyclin-dependent kinases (CDKs) are the catalytic subunits of a large family of serine/threonine protein kinases that become activated when associated with regulatory proteins, primarily cyclins. CDKs are pivotal for the correct timing of cell cycle progression and are responsible for mediating transcription events. There are currently twenty known mammalian CDKs, with CDK7--CDK13 primarily being linked to transcription and CDK 1, 2, 4, and 6 having principal implications in cell cycle management. Cancers show' direct or indirect deregulation of CDKs, therefore targeting CDKs is an important mode to develop new_' anticancer therapeutics. Indeed, CDK inhibitor drugs have shown great promise in clinical settings. See e.g., Trends in Molecular Medicine. 8 (4 Supp1): S32-7. Given the continuing medical need for cancer therapeutics, additional CDK inhibitors are needed.

SUMMARY

Provided herein are compounds having the Formula I:

and pharmaceutically acceptable salts and compositions thereof, wherein R¹, R², R^nl and ring A are defined herein. The disclosed compounds and pharmaceutically acceptable salts thereof, and compositions comprising such, modulate (e.g., inhibit) cyclin-dependent kinases (CDKs) and are useful in treating a variety of cancers.

The provided compounds can be used alone (i.e., as a monotherapy) or in combination with one or more other therapeutic agent effective for treating any of the indications described herein. DETAILED DESCRIPTION

The details of construction and the arrangement of components set forth in the following description or illustrated in the drawings are not meant to be limiting. Embodiments can be practiced or carried out in various ways. The phraseology and terminology used herein is for purpose of description and should not be regarded as limiting.

General Description of Compounds

In one aspect, provided is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein Ring A is 5- or 6-membered heteroaryl or 5- or 6-membered heterocyclyl, each of which is substituted with 0-4 occurrences of R^a;

R¹ is -NRⁿ²R⁴ and R² is -L'-R³; or R¹ is L°-Ring B-L¹-R³ and R² is hydrogen or C1-C6 alkyl;

L° is a bond or C1-C3 hydrocarbon chain, wherein one or more carbon units of the hydrocarbon chain is optionally replaced with -O-, -S-, -NRⁿ³-, -NRⁿ³C(=O)-, - C(=O)NRⁿ³-, -NRⁿ³C(=O)O-, -OC(=O)NRⁿ³-, - NR^nlC(=O)NRⁿ³-, -C(=O)-, -OC(=O)-, or -C(=O)O-; each instance of L¹ is independently a-(CH₂)_x -[(CH₂)_m O]_n -(CH₂)_y- L² ; a indicates the point of attachment to Ring A or Ring B;

L² is attached to R³; x is 0 or an integer from 1 to 10 included; each instance of m is independently 0 or an integer from 1 to 10 included; n is 0 or an integer from 1 to 15 included; y is 0 or an integer from 1 to 10 included;

L² is a bond, -O-, -S-, -NRⁿ³-, -C(=O)-, -OC(=O)-, -C(=O)O-, - NRⁿ³C(=O)-, -C(=O)NRⁿ³-, -NRⁿ³C(=O)O-, -OC(=O)NRⁿ³-, - NRⁿ³C(=O)NRⁿ³-, - NRⁿ³C(=O)CH₂O-, or -OCH₂C(=O)NRⁿ³-; and Ring B is 5- or 6-membered heteroaryl or phenyl, each of which is substituted with 0- 4 occurrences of R^b; each instance of R³ is independently selected from one of the following formulae:

each instance of R⁴ is independently C₁-C₄ alkylene-heteroaryl or C₁-C₄ alkylene-aryl, wherein each of the heteroaryl or aryl is substituted with 0-4 occurrences of R^c; each instance of R^a, R^b, and R^c is independently halogen, hydroxyl, or C₁-C₆ alkyl; each instance of R^nl, Rⁿ², and Rⁿ³ is independently hydrogen, C₁-C₆ alkyl, or a nitrogen protecting group; and

R^o1 is hydrogen, C₁-C₆ alkyl, or an oxygen protecting group.

Definitions

Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen etal., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

The compounds described herein may exist in various tautomeric forms. The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds/ substituents resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations. The present teachings encompass compounds in the form of tautomers, which includes forms not depicted structurally. All such isomeric forms of such compounds are expressly included. If a tautomer of a compound is aromatic, this compound is aromatic. Similarly, if a tautomer of a compound is a heteroaryl, this compound is heteroaryl. It is to be understood that when a compound herein is represented by a structural formula or designated by a chemical name herein, all other tautomeric forms which may exist for the compound are encompassed by the structural formula.

The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C_1-10 alkyl”). Examples of Ci-₆ alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., «-propyl, isopropyl), butyl (C4)

(e.g., «-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., «-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C₆) (e.g., «-hexyl).

The term “halo” or “halogen” refers to fluorine, chlorine, bromine, or iodine.

The term “5- or 6-membered heterocyclyl” or “ 5- or 6-membered heterocyclic” refers to a radical of a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.

Exemplary heterocyclyl groups include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-2,5-dine, dioxolanyl, oxathiolanyl, dithiolanyl, triazolinyl, oxadiazolinyl, thiadiazolinyl, piperidinyl, tetrahydropyranyl, dihydropyridinyl, thianyl, piperazinyl, morpholinyl, piperidinyl, dithianyl, dioxanyl, triazinanyl, and the like.

The term “5- or 6-membered heteroaryl” refers to a 5- or 6-membered monocyclic and unfused 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. Exemplary monocyclic 5- or 6- membered heteroaryl groups include pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and tetrazinyl. In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.

Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the active agent is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (cupric and cuprous), ferric, ferrous, lithium, magnesium, manganese (manganic and manganous), potassium, sodium, zinc and the like salts. Particular salts are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N’,N’- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylameine, trimethylamine, tripropylamine, tromethamine and the like.

The terms “composition” and “formulation” are used interchangeably.

As used herein, the term "patient" or “subject” refers to a human in need of treatment with a compound described herein for any purpose, in particular a human in need of such a treatment to treat cancer, or a precancerous condition or lesion. However, the term "patient" or “subject” can also refer to non-human animals, in particular mammals such as dogs, cats, horses, cows, pigs, sheep and non-human primates, among others, that are in need of treatment with a compound described herein.

The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.

The term "treating" as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing, either partially or completely, the growth of tumors, tumor metastases, or other cancer-causing or neoplastic cells in a patient. The term "treatment" as used herein, unless otherwise indicated, refers to the act of treating. A “method of treating cancer” refers to a procedure or course of action that is designed to reduce or eliminate the number of cancer cells in an animal, or to alleviate the symptoms of a cancer. The terms “condition,” “disease,” and “disorder” are used interchangeably.

The term "effective amount" or "effective amount" means the amount of a compound described herein or a compound described herein in combination with another drug that will elicit the biological or medical response of a tissue, system or animal e.g. human that is being sought. In an embodiment, the response is inhibition of tumor volume or the rate of increase in tumor volume over time, for example, static volume or decreased volume. In another embodiment, an effective amount is the amount of a disclosed compound that reduces the number of cancer cells or that reduces the rate of increase in number of cancer cells. In another embodiment, an effective amount is the amount of a disclosed compound sufficient to cause differentiation of at least a portion of the cancer cells, for example, in hematological tumors the conversion of undifferentiated blast cells to functional neutrophils. A therapeutically effective amount does not necessarily mean that the cancer cells will be entirely eliminated or that the number of cells will be reduced to zero or undetectable, or that the symptoms of the cancer will completely be alleviated. In one aspect, the effective amount is from 0.001 to 100 mg/kg of body weight per day or per week in single or divided doses, or by continuous infusion.

Description of Exemplary Compounds

In a first embodiment, provided is a compound Formula I:

or a pharmaceutically acceptable salt thereof, wherein the variables are as described above. In a second embodiment, the compound of Formula I is of Formula II:

or a pharmaceutically acceptable salt thereof , wherein the remaining variables are as described above for Formula I.

In a second embodiment, the compound of Formula I is of Formula Il-a:

or a pharmaceutically acceptable salt thereof , wherein the remaining variables are as described above for Formula I. In a third embodiment, the compound of Formula I is of Formula Il-b:

or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for Formula I. In a fourth embodiment, the compound of Formula I is of Formula II-c:

or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for Formula I. In a fifth embodiment, the compound of Formula I is of Formula Il-d:

or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for Formula I.

In a sixth embodiment, the compound of Formula I is of Formula III:

In a seventh embodiment, the compound of Formula I is of Formula Ill-a:

In an eighth embodiment, the compound of Formula I is of Formula Ill-b:

In a ninth embodiment, R³ in any one of Formulae I, II, Il-a, Il-b, II-c, Il-d, III, III- a, and Illb, or a pharmaceutically acceptable salt thereof, is of formula i: wherein the remaining variables are as described above for

In a tenth embodiment, R³ in any one of Formulae I, II, Il-a, Il-b, II-c, Il-d, III, III- a, and Illb, or a pharmaceutically acceptable salt thereof, is of formula ii: wherein the remaining variables are as described above for

Formula I.

In an eleventh embodiment, Ring A in any one of Formulae I, II, Il-a, Il-b, II-c, Il-d, and III, or a pharmaceutically acceptable salt thereof, is pyrazolyl, pyridinyl, or pyridinyl-2- one, each of which is substituted with 0-4 occurrences of R^a, wherein the remaining variables are as described above for Formula I or the ninth or tenth embodiments. Alternatively, as part of an eleventh embodiment, Ring A in any one of Formulae I, II, Il-a, Il-b, II-c, Il-d, and III, or a pharmaceutically acceptable salt thereof, is pyrazolyl, pyridinyl, or pyridinyl-2-one, each of which is unsubstituted, wherein the remaining variables are as described above for Formula I or the ninth or tenth embodiments.

In a twelfth embodiment, ^a-(CH₂)_x - [ (CH₂)_m O]_n -(CH₂)_y- in any one of Formulae I, II, Il-a, Il-b, II-c, Il-d, III, Ill-a, and Illb, or a pharmaceutically acceptable salt thereof, is (CH₂)zi-(CH₂OCH₂)z2- or ⁱ'-(OCH₂CH₂)zi-(CH₂)z2; wherein each instance of zl and z2 is independently 0 or an integer from 1 to 10 included, wherein the remaining variables are as described above for Formula I or the ninth, tenth, or eleventh embodiments. Alternatively, as part of a twelfth embodiment, ^a-(CH₂)_x - [ (CH₂) _m O]_n - (CH₂)_y- in any one of Formulae I, II, II- a, Il-b, II-c, Il-d, III, Ill-a, and Illb, or a pharmaceutically acceptable salt thereof, is selected from one of the following formulae: ^a-(CH₂)₂OCH₂-, ^a-(CH₂)₃OCH₂-, ^a- (CH₂)₄OCH₂-, ^a-(CH₂O)₂CH₂-, ^a-(CH₂O)₃CH₂-, ^a-(CH₂O)₄CH₂-, ^a-(CH₂O)₅CH₂-, ^a- (CH₂O)₆CH₂-, ^a-(CH₂O)₃(CH₂)2-, ^a-(CH₂CH₂O)₃CH₂-, ^a-(CH₂CH₂O)₄CH₂-, ^a- (CH₂CH₂O)5CH₂-, ^a-(CH₂CH₂O)6CH₂-, ^a-[(CH₂)₄O]₂CH₂-, ^a-CH₂(CH₂CH₂O)₂CH₂-, ^a- CH₂(CH₂CH₂O)2(CH₂)2-, ^a-CH₂(CH₂CH₂O)₄CH₂-, ^a-CH₂[(CH₂)₄O]₃CH₂-, ^a- (CH₂)2[(CH₂)2O]5CH₂-, ^a-(CH₂)2(CH₂CH₂O)5CH₂-, ^a-(CH₂)2(CH₂CH₂O)2CH₂-, ^a- (CH₂O)₂(CH₂)₄OCH₂-, ^a-(CH₂)₄O-(CH₂)₃O(CH₂)₄OCH₂-, ^a-

(CH₂)₂(CH₂CH₂O)₅[(CH₂)₄O]CH₂-, ^a-(CH₂CH₂O)₂[(CH₂)₄O]CH₂-, ^a-[(CH₂)₄O] [(CH₂)₃O] [(CH₂)₄O]CH₂-, -O(CH₂)₂-, -O(CH₂)₃-, -O(CH₂)₄-, -O(CH₂)₂O-, -O(CH₂)₃O-, -O(CH₂)₄O-, ^a- OCH₂ CH₂OCH₂-, ^a-O(CH₂CH₂O)₂CH₂-, ^a-O(CH₂CH₂O)₃CH₂-, ^a-O(CH₂CH₂O)₄CH₂-, ^a- O(CH₂CH₂O)₅CH₂-, ^a-O(CH₂CH₂O)₆CH_2, ^a-OCH₂CH₂O(CH₂)₂-, ^a-O(CH₂CH₂O)₂(CH₂)₂-, ^a- O(CH₂CH₂O)₃(CH₂)₂-, ^a-O(CH₂CH₂O)₄(CH₂)₂- , ^a-O(CH₂CH₂O)₅(CH₂)₂-, ^a- O(CH₂CH₂O)₆(CH₂)_2-, ^a-OCH₂CH₂O(CH₂)₃-, ^a-O(CH₂CH₂O)₂(CH₂)₃-, ^a- O(CH₂CH₂O)₃(CH₂)₃-, ^a-O(CH₂CH₂O)₄(CH₂)₃- , ^a-O(CH₂CH₂O)₅(CH₂)₃-, ^a- O(CH₂CH₂O)₆(CH₂)₃-, ^a-0 CH₂CH₂O(CH₂)₄-, ^a-O(CH₂CH₂O)₂(CH₂)₄-, ^a- O(CH₂CH₂O)₃(CH₂)4-, ^a-O(CH₂CH₂O)₄(CH₂)4- , ^a-O(CH₂CH₂O)5(CH₂)₄-, ^a- O(CH₂CH₂O)₆(CH₂)4-, ^a-OCH₂CH₂O(CH₂)₄O(CH₂)4- , ^a-OCH₂CH₂O(CH₂)₄O(CH₂)5-, ^a- OCH₂CH₂O[(CH₂)₄O]₂(CH₂)4-, ^a-OCH₂CH₂O[(CH₂)₄O]₂(CH₂)5-, ^a- OCH₂CH₂O[(CH₂)₄O][(CH₂)₂O](CH₂)₂-, ^a-OCH₂CH₂O[(CH₂)₄O][(CH₂)₂O](CH₂)4-, OCH₂CH₂O[(CH₂)₄O][(CH₂)₃O](CH₂)₂-, ^a-OCH₂CH₂O[(CH₂)₄O][(CH₂)₃O](CH₂)4-, OCH₂CH₂O[(CH₂)4O][(CH₂)4O](CH₂)₂-, ^a-OCH₂CH₂O[(CH₂)4O][(CH₂)₄O](CH₂)4-, ^a- OCH₂CH₂O[(CH₂)₄O][(CH₂)₂O](CH₂)₄CH₂-, or ^a- OCH₂CH₂O[(CH₂)₄O][(CH₂)₂O](CH₂)₄(CH₂)₂-, wherein the remaining variables are as described above for Formula I or the ninth, tenth, or eleventh embodiments.

In a thirteenth embodiment, R⁴ in any one of Formulae I, II, Il-a, Il-b, II-c, and Il-d, or a pharmaceutically acceptable salt thereof, is CH₃, C₂H₅, or benzyl, wherein the remaining variables are as described above for Formula I or the ninth, tenth, eleventh, or twelfth embodiments.

In a fourteenth embodiment, Ring B in any one of Formulae I, Ill-a and Ill-b, or a pharmaceutically acceptable salt thereof, is pyrazolyl or phenyl, each of which is substituted with 0- 1 occurrences of R^b, wherein the remaining variables are as described above for Formula I or the ninth, tenth, eleventh, twelfth, or thirteenth embodiments. Alternatively, as part of a fourteenth embodiment, Ring B in any one of Formulae I, Ill-a and Ill-b, or a pharmaceutically acceptable salt thereof, is pyrazolyl or phenyl, each of which is unsubstituted, wherein the remaining variables are as described above for Formula I or the ninth, tenth, eleventh, twelfth, or thirteenth embodiments.

In a fifteenth embodiment, R^o1 in any one of Formulae I, II, Il-a, Il-b, II-c, Il-d, III, Ill-a, and Illb, or a pharmaceutically acceptable salt thereof, is hydrogen or CH₃, wherein the remaining variables are as described above for Formula I or the tenth, eleventh, twelfth, thirteenth, or fourteenth embodiments. In a sixteenth embodiment, R^nl in any one of Formulae I, II, Il-a, Il-b, II-c, Il-d, III, Ill-a, and Illb, or a pharmaceutically acceptable salt thereof, is hydrogen or CH3, wherein the remaining variables are as described above for Formula I or the ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiments. In a seventeenth embodiment, Rⁿ² in any one of Formulae I, II, Il-a, Il-b, II-c, Il-d,

III, Ill-a, and Illb, or a pharmaceutically acceptable salt thereof, is hydrogen or CH3, wherein the remaining variables are as described above for Formula I or the ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiments.

In an eighteenth embodiment, Rⁿ³ in any one of Formulae I, II, Il-a, Il-b, II-c, Il-d, III, Ill-a, and Illb, or a pharmaceutically acceptable salt thereof, is hydrogen or CH3, wherein the remaining variables are as described above for Formula I or the ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiments.

In another embodiment, the invention is any one of the compounds from Table 1 and in the Examples, or a pharmaceutical acceptable salt thereof. In Table 1, a compound described herein may have an IC50 of CDK12 (see Example

17). “A” refers to an IC50 less than 0.300 mM; “B” refers to an IC50 from 0.301 pM to 0.800 pM, and “C” refers to an IC50 greater than 0.800 pM.

Table 1. Exemplary compounds and activities against CDK12/Cyclin K

In Table 2, a compound described herein were further tested in E3 ligase engagement assay (Example 18) and CDK12 degradation assay (Example 19). In the E3 ligase engagement assay, Cell VHL (mM) or Cell CRBN (pM), “AA” refers to an AC50 less than or equal to 1 pM; and “BB” refers to an AC50 more than 1 pM. NA means not available. Best- fit IC 50, “+++” refers to an IC50 less than 0.500 pM; “++” refers to an IC50 from 0.501 pM to 1.0 pM, and “+” refers to an IC50 greater than 1.0 pM. In the CDK12 degradation assay, Best-fit max (%degradation): “***” refers to 100%- 50%;

refers to 49%-20%,

refers to “0-19%”.

Table 2. Exemplified compounds from Table 1 in the E3 ligase engagement assay and

CDK12 degradation assay.

Specific examples of compounds are provided in the EXEMPLIFICATION section and are included as part of a fourteenth embodiment herein. Pharmaceutically acceptable salts as well as the neutral forms of the compounds in the EXEMPLIFICATION are also included.

Uses. Formulation, and Administration

According to another aspect, provided are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The term “pharmaceutically acceptable carrier” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.

Pharmaceutically acceptable compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.

Other modes of administration are contemplated and include e.g., orally, parenterally, by inhalation spray, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

Methods of preparing pharmaceutical compositions such as those described above are known in the art, and for example are described, in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 18^th edition (1990). For oral administration, tablets containing a compound described herein, and optionally with another active agent, are combined with any of various excipients such as, for example, micro-crystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, along with various disintegrants such as starch (such as com, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinyl pyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tableting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; particular materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the inhibitor may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof. For parenteral administration of either or both of the active agents, solutions in either sesame or peanut oil or in aqueous propylene glycol may be employed, as well as sterile aqueous solutions comprising the active agent or a corresponding water-soluble salt thereof. Such sterile aqueous solutions may be suitably buffered, and also may be rendered isotonic, e.g., with sufficient saline or glucose. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art. Any parenteral formulation selected for administration of proteinaceous inhibitors should be selected so as to avoid denaturation and loss of biological activity of the inhibitor.

The amount of compounds described herein that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated and the particular mode of administration. In some embodiments, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor, such as e.g., 0.1 - 100 mg/kg body weight/day, can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound described herein in the composition will also depend upon the particular compound in the composition.

In some aspects, compounds and compositions described herein are useful in treating diseases and/or disorders associated with CDK and/or expression of a mutant form of CDK.

In some aspects, the disease responsive to a compound or composition described herein is a cancer. Thus, provided herein are methods for treating cancer in a subject (e.g., by inhibiting CDK12 in said subject) comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. Also provided is a compound described herein, or a pharmaceutically acceptable salt thereof for use in treating cancer in a subject. Further provided is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject. Further provided is the use of a compound described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating cancer.

“Cancer” in a mammal refers to the presence of cells possessing characteristics typical of cancers, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain characteristic morphological features. The term cancer and tumor is used herein interchangeably. Often, cancer cells will be in the form of a solid tumor, but such cells may exist alone within an animal, or may circulate in the blood stream as independent cells, such as leukemic cells. In the methods described herein, the cancer cell can be any tissue type, for example, cholangiocarcinoma, pancreatic, lung, bladder, breast, esophageal, colon, ovarian. In another embodiment, cancer is selected from the group consisting of glioblastoma (glioma), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute myelogenous leukemia (AML), sarcoma, melanoma, non-small cell lung cancer, chondrosarcoma, cholangiocarcinomas and angioimmunoblastic lymphoma. In another embodiment the cancer is glioma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute myelogenous leukemia (AML), melanoma, chondrosarcoma, or angioimmunoblastic non-Hodgkin’s lymphoma (NHL). The cancer is any cancer treatable, either partially or completely, by administration of a CDK12 inhibitor. The cancer may be, for example, lung cancer, non-small cell lung (NSCL) cancer, bronchioloalviolar cell lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, mesothelioma, hepatocellular cancer, biliary cancer, chronic or acute leukemia, lymphocytic lymphomas, neoplasms of the central nervous system (CNS), spinal axis tumors, brain stem glioma, glioblastoma multiforme, astrocytomas, schwannomas, ependymomas, medulloblastomas, meningiomas, squamous cell carcinomas, pituitary adenomas, including refractory versions of any of the above cancers, or a combination of one or more of the above cancers. The precancerous condition or lesion includes, for example, the group consisting of oral leukoplakia, actinic keratosis (solar keratosis), precancerous polyps of the colon or rectum, gastric epithelial dysplasia, adenomatous dysplasia, hereditary nonpolyposis colon cancer syndrome (HNPCC), Barrett's esophagus, bladder dysplasia, and precancerous cervical conditions. In a particular embodiment, the cancer is glioblastoma multiforme. In a particular embodiment, the cancer is breast cancer. In a particular embodiment, the cancer is bladder cancer. In a particular embodiment, the cancer is prostate cancer. In a particular embodiment, the cancer is melanoma. In a particular embodiment, the cancer is endometrial carcinoma.

A disclosed compound may be administered in combination with cytotoxic, chemotherapeutic or anti-cancer agents, including for example: alkylating agents or agents with an alkylating action, such as cyclophosphamide (CTX; e.g. CYTOXAN®), chlorambucil (CHL; e.g. LEUKERAN®), cisplatin (CisP; e.g. PLATINOL®) busulfan (e.g. MYLERAN®), melphalan, carmustine (BCNU), streptozotocin, triethylenemelamine (TEM), mitomycin C, and the like; antibiotics, such as actinomycin D, doxorubicin (DXR; e.g. ADRIAMYCIN®), daunorubicin (daunomycin), bleomycin, mithramycin and the like; alkaloids, such as vinca alkaloids such as vincristine (VCR), vinblastine, and the like; and other antitumor agents, such as paclitaxel (e.g. TAXOL®) and paclitaxel derivatives, the cytostatic agents, glucocorticoids such as dexamethasone (DEX; e.g. DECADRON®) and corticosteroids such as prednisone, nucleoside enzyme inhibitors such as hydroxyurea, amino acid depleting enzymes such as asparaginase, leucovorin and other folic acid derivatives, and similar, diverse antitumor agents. The following agents may also be used as additional agents: amifostine (e.g. ETHYOL®), dactinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, lomustine (CCNU), doxorubicin lipo (e.g. DOXIL®), gemcitabine (e.g. GEMZAR®), daunorubicin lipo (e.g. DAUNOXOME®), procarbazine, mitomycin, docetaxel (e.g. TAXOTERE®), aldesleukin, carboplatin, oxaliplatin, cladribine, camptothecin, CPT 11 (irinotecan), 10-hydroxy 7-ethyl-camptothecin (SN38), floxuridine, fludarabine, ifosfamide, idarubicin, mesna, interferon beta, interferon alpha, mitoxantrone, topotecan, leuprolide, megestrol, melphalan, mercaptopurine, plicamycin, mitotane, pegaspargase, pentostatin, pipobroman, plicamycin, tamoxifen, teniposide, testolactone, thioguanine, thiotepa, uracil mustard, vinorelbine, chlorambucil. The present disclosure further provides methods for treating tumors in a patient, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, and in addition, simultaneously or sequentially, one or more anti-hormonal agents. As used herein, the term "anti-hormonal agent" includes natural or synthetic organic or peptidic compounds that act to regulate or inhibit hormone action on tumors. Antihormonal agents include, for example: steroid receptor antagonists, anti-estrogens such as tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, other aromatase inhibitors, 42-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (e.g. FARESTON®); anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above; agonists and/or antagonists of glycoprotein hormones such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and luteinizing hormone (LH) and LHRH (leuteinizing hormone-releasing hormone); the LHRH agonist goserelin acetate, commercially available as ZOLADEX® (AstraZeneca); the LHRH antagonist D-alaninamide N-acetyl-3-(2-naphthalenyl)-D-alanyl-4- chloro-D-phenylalanyl-3-(3-pyridinyl)-D-alanyl-L-seryl-N6-(3-pyridinylcarbonyl)-L-lysyl- N6-(3-pyridinylcarbonyl)-D-lysyl-L-leucyl-N6-(l-methylethyl)-L-lysyl -L-proline (e.g ANTIDE®, Ares-Serono); the LHRH antagonist ganirelix acetate; the steroidal anti- androgens cyproterone acetate (CPA) and megestrol acetate, commercially available as MEGACE® (Bristol-Myers Oncology); the nonsteroidal anti-androgen flutamide (2-methyl- N-[4, 20-nitro-3-(trifluoromethyl) phenylpropanamide), commercially available as EULEXIN® (Schering Corp.); the non-steroidal anti-androgen nilutamide, (5,5-dimethyl-3- [4-nitro-3-(trifluoromethyl-4’-nitrophenyl)-4,4-dimethyl-imidazolidine-dione); and antagonists for other non-permissive receptors, such as antagonists for RAR, RXR, TR,

VDR, and the like.

The use of the cytotoxic and other anticancer agents described above in chemotherapeutic regimens is generally well characterized in the cancer therapy arts, and their use herein falls under the same considerations for monitoring tolerance and effectiveness and for controlling administration routes and dosages, with some adjustments. For example, the actual dosages of the cytotoxic agents may vary depending upon the patient's cultured cell response determined by using histoculture methods. Generally, the dosage will be reduced compared to the amount used in the absence of additional other agents. Typical dosages of an effective cytotoxic agent can be in the ranges recommended by the manufacturer, and where indicated by in vitro responses or responses in animal models, can be reduced by up to about one order of magnitude concentration or amount. Thus, the actual dosage will depend upon the judgment of the physician, the condition of the patient, and the effectiveness of the therapeutic method based on the in vitro responsiveness of the primary cultured malignant cells or histocultured tissue sample, or the responses observed in the appropriate animal models.

The present disclosure further provides methods for treating tumors or tumor metastases in a patient, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, and in addition, simultaneously or sequentially, one or more angiogenesis inhibitors. Anti- angiogenic agents include, for example: VEGFR inhibitors, such as SU-5416 and SU-6668 (Sugen Inc. of South San Francisco, Calif., USA), or as described in, for example International Application Nos. WO 99/24440, WO 99/62890, WO 95/21613, WO 99/61422, WO 98/50356, WO 99/10349, WO 97/32856, WO 97/22596, WO 98/54093, WO 98/02438, WO 99/16755, and WO 98/02437, and U.S. Patent Nos. 5,883,113, 5,886,020, 5,792,783, 5,834,504 and 6,235,764; VEGF inhibitors such as IM862 (Cytran Inc. of Kirkland, Wash., USA); angiozyme, a synthetic ribozyme from Ribozyme (Boulder, Colo.) and Chiron (Emeryville, Calif.); and antibodies to VEGF, such as bevacizumab (e.g. AVASTIN™, Genentech, South San Francisco, CA), a recombinant humanized antibody to VEGF; integrin receptor antagonists and integrin antagonists, such as to a_vβ_3, α_vβ₅ and α_vβ₆ integrins, and subtypes thereof, e.g. cilengitide (EMD 121974), or the anti-integrin antibodies, such as for example a_nβ3 specific humanized antibodies (e.g. VITAXIN®); factors such as IFN-alpha (U.S. Patent Nos. 41530,901, 4,503,035, and 5,231,176); angiostatin and plasminogen fragments (e.g. kringle 1-4, kringle 5, kringle 1-3 (O'Reilly, M. S. et al. (1994) Cell 79:315- 328; Cao et al. (1996) J. Biol. Chem. 271: 29461-29467; Cao et al. (1997) J. Biol. Chem. 272:22924-22928); endostatin (O'Reilly, M. S. et al. (1997) Cell 88:277; and International Patent Publication No. WO 97/15666); thrombospondin (TSP-1; Frazier, (1991) Curr. Opin. Cell Biol. 3:792); platelet factor 4 (PF4); plasminogen activator/urokinase inhibitors; urokinase receptor antagonists; heparinases; fumagillin analogs such as TNP-4701; suramin and suramin analogs; angiostatic steroids; bFGF antagonists; flk-1 and fit- 1 antagonists; anti- angiogenesis agents such as MMP-2 (matrix-metalloproteinase 2) inhibitors and MMP-9 (matrix-metalloproteinase 9) inhibitors. Examples of useful matrix metalloproteinase inhibitors are described in International Patent Publication Nos. WO 96/33172, WO 96/27583, WO 98/07697, WO 98/03516, WO 98/34918, WO 98/34915, WO 98/33768, WO 98/30566, WO 90/05719, WO 99/52910, WO 99/52889, WO 99/29667, and WO 99/07675, European Patent Publication Nos. 818,442, 780,386, 1,004,578, 606,046, and 931,788; Great Britain Patent Publication No. 9912961, and U.S. patent Nos. 5,863,949 and 5,861,510. Particular MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. Others, are those that selectively inhibit MMP-2 and/or MMP-9 relative to the other matrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP- 8, MMP-10, MMP-11, MMP-12, and MMP-13).

The present disclosure further provides methods for treating tumors or tumor metastases in a patient, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, and in addition, simultaneously or sequentially, one or more tumor cell pro-apoptotic or apoptosis- stimulating agents. The present disclosure further provides methods for treating tumors or tumor metastases in a patient, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, and in addition, simultaneously or sequentially, one or more signal transduction inhibitors. Signal transduction inhibitors include, for example: erbB2 receptor inhibitors, such as organic molecules, or antibodies that bind to the erbB2 receptor, for example, trastuzumab (e.g. HERCEPTIN®); inhibitors of other protein tyrosine-kinases, e.g. imitinib (e.g. GLEEVEC®); ras inhibitors; raf inhibitors (e.g. BAY 43-9006, Onyx Pharmaceuticals/Bayer Pharmaceuticals); MEK inhibitors; mTOR inhibitors; cyclin dependent kinase inhibitors; protein kinase C inhibitors; and PDK-1 inhibitors (see Dancey, J. and Sausville, E.A. (2003) Nature Rev. Drug Discovery 2:92-313, for a description of several examples of such inhibitors, and their use in clinical trials for the treatment of cancer).

ErbB2 receptor inhibitors include, for example: ErbB2 receptor inhibitors, such as GW- 282974 (Glaxo Wellcome pic), monoclonal antibodies such as AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Tex., USA) and 2B-1 (Chiron), and erbB2 inhibitors such as those described in International Publication Nos. WO 98/02434, WO 99/35146, WO 99/35132, WO 98/02437, WO 97/13760, and WO 95/19970, and U.S. Patent Nos. 5,587,458, 5,877,305, 6,465,449 and 6,541,481.

The present disclosure further provides methods for treating tumors or tumor metastases in a patient, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, and in addition, simultaneously or sequentially, one or more additional anti-proliferative agents. Additional antiproliferative agents include, for example: Inhibitors of the enzyme farnesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFR, including the compounds disclosed and claimed in U.S. patent Nos. 6,080,769, 6,194,438, 6,258,824, 6,586,447, 6,071,935, 6,495,564, 6,150,377, 6,596,735 and 6,479,513, and International Patent Publication WO 01/40217.

The present disclosure further provides methods for treating tumors or tumor metastases in a patient, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, and in addition, simultaneously or sequentially, treatment with radiation or a radiopharmaceutical. The source of radiation can be either external or internal to the patient being treated. When the source is external to the patient, the therapy is known as external beam radiation therapy (EBRT). When the source of radiation is internal to the patient, the treatment is called brachytherapy (BT). Radioactive atoms for use in the context of this invention can be selected from the group including, but not limited to, radium, cesium-137, iridium-192, americium-241, gold-198, cobalt-57, copper-67, technetium-99, iodine-123, iodine-131, and indium-111. Where the CDK12 inhibitor according to this invention is an antibody, it is also possible to label the antibody with such radioactive isotopes. Radiation therapy is a standard treatment for controlling unresectable or inoperable tumors and/or tumor metastases. Improved results have been seen when radiation therapy has been combined with chemotherapy. Radiation therapy is based on the principle that high-dose radiation delivered to a target area will result in the death of reproductive cells in both tumor and normal tissues. The radiation dosage regimen is generally defined in terms of radiation absorbed dose (Gy), time and fractionation, and must be carefully defined by the oncologist. The amount of radiation a patient receives will depend on various considerations, but the two most important are the location of the tumor in relation to other critical structures or organs of the body, and the extent to which the tumor has spread. A typical course of treatment for a patient undergoing radiation therapy will be a treatment schedule over a 1 to 6 week period, with a total dose of between 10 and 80 Gy administered to the patient in a single daily fraction of about 1.8 to 2.0 Gy, 5 days a week. In a particular embodiment of this invention there is synergy when tumors in human patients are treated with the combination treatment of the invention and radiation. In other words, the inhibition of tumor growth by means of the agents comprising the combination of the invention is enhanced when combined with radiation, optionally with additional chemotherapeutic or anticancer agents. Parameters of adjuvant radiation therapies are, for example, contained in International Patent Publication WO 99/60023. The present disclosure further provides methods for treating tumors or tumor metastases in a patient, comprising administering to the patient a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, and in addition, simultaneously or sequentially, treatment with one or more agents capable of enhancing antitumor immune responses. Agents capable of enhancing antitumor immune responses include, for example: CTLA4 (cytotoxic lymphocyte antigen 4) antibodies (e.g. MDX-CTLA4), and other agents capable of blocking CTLA4. Specific CTLA4 antibodies that can be used in the present invention include those described in U.S. Patent No.

6,682,736.

EXEMPLIFICATION

Abbreviations list

General experimental

In the following examples, the chemical reagents were purchased from commercial sources (such as Alfa, Acros, Sigma Aldrich, TCI and Shanghai Chemical Reagent Company), and used without further purification. Flash chromatography was performed on a CombiFlashRf 150 (ISCO) via column with silica gel particles of 200-300 mesh. Analytical and preparative thin layer chromatography plates (TLC) were HSGF 254 (0.15-0.2mm thickness, Shanghai Anbang Company, China). Nuclear magnetic resonance (NMR) spectra were recorded using Bruker. AMX-400 NMR (Bruker, VARIAN) at around 20 - 30°C unless otherwise specified. The following abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublets; ddd, doublet of doublet of doublets; dt, doublet of triplets; br s, broad signal. Chemical shifts were reported in parts per million (ppm, d) downfield from tetramethylsilane. Mass spectra were run with electrospray ionization (ESI) from a Waters LCT TOF Mass Spectrometer (Waters, USA). Compound purification was carried out as needed using a variety of traditional methods including, but not limited to, preparative chromatography under acidic, neutral, or basic conditions using either normal phase or reverse phase HPLC or flash columns or Prep-TLC plates.

Preparative HPLC: unless otherwise described, the compounds were purified using a GILSON GX-281 system equipped with a Phenomenex Gemini NX-C18 Column (5 pm, 110A, 150 x 30 mm) or equivalent and the following solvent system: ¾O, AcCN, and 1% ammonia in H2O. Specific elution gradients were based on the retention times obtained with an analytical LC-MS, however, in general all elution gradients of H2O and MeCN were run over a 12 minute run time with a flow rate of 30 mL/min.

Analytical LC-MS: (Acid condition) analytical LC-MS was performed on a Agilent 1200 Series HPLC& single quadmpole MSD and ELSD instrument equipped with a Waters Xbridge-C18 column (50x2mm, 5pm ), a column temperature of 40 °C or 50°C and using the following solvent system: Solvent A: 0.04 % TFA in H2O; and Solvent B: 0.02 % TFA in ACN. All compounds were run using 4.5min gradient methods with a flow rate of 0.6 mL/min or 0.8mL/min. Actual gradient will depend on the polarity of compound.

(Basic condition) analytical LC-MS was performed on a Agilent 1200 Series HPLC& single quadmpole MSD and ELSD instrument equipped with a Waters Xbridge Shield RP18 column (50x2. lmm, 5pm ), a column temperature of 40 °C and using the following solvent system: Solvent A: 0.05 % NH3.H2O in H2O; and Solvent B: ACN. All compounds were run using 4.5min gradient methods with a flow rate of 0.6 mL/min or 0.8mL/min. Actual gradient will depend on the polarity of compound.

Preparative Chiral SFC Separation: stereoisomer mixtures were separated using a Berger MultiGram SFC/ Waters Thar 80 instrument on one of the following columns: ChiralPak AS-H (30 x 250 mm), eluting with either 0.1 % NH3H2O in MeOH / CO₂, or 0.1 % 0.1 % NH3H2O in EtOH / CO2 or 0.1 %0.1 % NH3H2O in isopropanol / CO2 with a flow rate of 50-80 mL/min and a column temperature of 38°C.

Analytical Chiral SFC Separation: stereoisomer mixtures or single enantiomers were analyzed using a Waters UPC2 or Agilent analytical SFC instrument on one of the following columns: ChiralPak AS-3 (4.6 x 150 mm), eluting with either 0.1 % diethylamine in MeOH / CO2, or 0.1 % diethylamine in EtOH / CO2 or 0.1 % diethylamine in isopropanol / CO2, with a flow rate of 2.5 imL/min and a column temperature of 35°C.

Scheme 1

Example 1. (2S,4R)-l-((S)-2-(2-(2-(4-(4-(3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)ureido)phenyl)-lH-pyrazol-l-yl)ethoxy)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide

Step A. Synthesis of ethyl 2-(2-(4-(4-(3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)ureido)phenyl)-lH-pyrazol-l-yl)ethoxy)acetate. To a solution of 1- (4-(lH-pyrazol-4-yl)phenyl)-3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)urea (100 mg, 203 umol) and ethyl 2-[2-(p- tolylsulfonyloxy)ethoxy] acetate (62 mg, 203 umol) in CH3CN (4 mL) was added CS2CO3 (133 mg, 407 umol). The mixture was stirred at 80 °C for 1 hr. The mixture was diluted with saturated brine (10 mL) and extracted with ethyl acetate (20 mL *3). The combined organic layer was washed with brine (15 mL), dried over Na₂SO₄, filtered and concentrated in vacuum to give a crude product. The crude product was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=l/0 to 1:1) to give the desired product ethyl 2-(2-(4-(4- (3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)phenyl)-lH-pyrazol- 1 -yl)ethoxy)acetate, 95 mg.

NMR (400 MHz, CDCl₃) d 8.26 (d, 1 H), 7.85 (s, 1 H), 7.78

(s, 1 H), 7.51 (d, 2 H), 7.44 (dd, 1 H), 7.25 - 7.29 (m, 2 H), 7.10 - 7.22 (m, 5 H), 6.25 (d, 1 H), 4.94 (br d, 1 H), 4.48 - 4.66 (m, 1 H), 4.32 - 4.44 (m, 5 H), 4.19 (q, 2 H), 4.04 (s, 2 H), 3.95 (t, 2 H), 3.49 (br s, 1 H), 2.09 (br d, 2 H), 1.97 (br d, 2 H), 1.29 - 1.45 (m, 7 H); LCMS [M+H]⁺: 622.3.

Step B. Synthesis of 2-(2-(4-(4-(3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)ureido)phenyl)-lH-pyrazol-l-yl)ethoxy)acetic acid. To a solution of ethyl 2- [2- [4- [4- [benzylcarbamoyl- [4- [(5-cyano-2- pyridyl)amino]cyclohexyl]amino]phenyl]pyrazol-l-yl]ethoxy]acetate (95 mg, 153 umol) in THF (4 mL) was added LiOH.H₂O (7 mg, 168 umol,) and H2O (1 mL). The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was cooled to 0°C and adjusted to pH =

6 with HC1 (1 M) solution. The resulting mixture was lyophilized in vacuum to give a crude product 2-[2-[4-[4-[benzylcarbamoyl-[4-[(5-cyano-2- pyridyl)amino]cyclohexyl]amino]phenyl]pyrazol-l-yl]ethoxy]acetic acid (100 mg, crude). LCMS [M+H]⁺: 594.3.

Step C. Synthesis of (2S,4R)-l-((S)-2-(2-(2-(4-(4-(3-benzyl-l-((lr,4r)-4-((5-cyanopyridin- 2-yl)amino)cyclohexyl)ureido)phenyl)-lH-pyrazol-l-yl)ethoxy)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide. To a mixture of 2-[2-[4-[4-[benzylcarbamoyl-[4-[(5-cyano-2- pyridyl)amino]cyclohexyl]amino]phenyl]pyrazol-l-yl]ethoxy]acetic acid (100 mg, 168.44 umol, 1 eq) and (2S,4R)-l-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4- methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (73 mg, 168 umol) in DMF (4 mL) was added HATU (96 mg, 253 umol) and TEA (51 mg, 505 umol, 70 uL), then the mixture was stirred at 25 °C for 17 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with saturated NaHCCL (15 mL) and extracted with ethyl acetate (30 mL *3). The organic layer was washed with brine (20 ml), dried over Na₂SO₄, filtered and evaporated to give a crude product. The crude product was purified by prep-HPLC(column: Boston Prime C18 150*30mm 5um; mobile phase: [water (10mM NH₄HCO₃) -ACN]; B%: 40%-70%, 8min) to give the desired product (2S,4R)- l-((S)-2-(2-(2-(4-(4-(3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)ureido)phenyl)-lH-pyrazol-l-yl)ethoxy)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, 38 mg.

l₃ 8.68 (s, 1 H), 8.27 (d, 1 H), 7.82 (s, 1 H), 7.75 (s, 1 H), 7.52 (d, 2 H), 7.46 (dd, 1 H), 7.33 - 7.41 (m, 4 H), 7.12 - 7.28 (m, 7 H), 6.28 (d, 1 H), 5.04 (d,

1 H), 4.72 (t, 1 H), 4.48 - 4.63 (m, 4 H), 4.33 - 4.44 (m, 6 H), 4.06 (d, 1 H), 3.89 - 4.00 (m, 4 H), 3.63 (dd, 1 H), 3.53 (br s, 1 H), 2.46 - 2.60 (m, 4 H), 2.06 - 2.18 (m, 3 H), 1.93 - 2.02 (m,

2 H), 1.23 - 1.50 (m, 4 H), 0.86 - 1.00 (m, 9 H); LCMS [M+H]⁺: 1006.4

The procedure set forth above in Example 1 was used to produce following compounds using appropriate starting materials. Standard protection and deprotection can be used when necessary.

Table I. Intermediates used in synthesizing Compound No. 1-1 to 1-16

Scheme 2

Example 2. 3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4-(l-(2-(2- (2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethoxy)ethyl)-lH-pyrazol-4-yl)phenyl)urea

Step A. Synthesis of 3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4- (l-(2-(2-(2-(2-(l,3-dioxoisoindolin-2-yl)ethoxy)ethoxy)ethoxy)ethyl)-lH-pyrazol-4- yl)phenyl)urea. To a mixture of 31-(4-(lH-pyrazol-4-yl)phenyl)-3-benzyl-l-((lr,4r)-4-((5- cyanopyridin-2-yl)amino)cyclohexyl)urea (160 mg, 303 umol, HC1 salt) and 2-(2-(2-(2-(l,3- dioxoisoindolin-2-yl)ethoxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (145 mg, 303 umol) in CH3CN (3 mL) was added CS2CO3 (197 mg, 606 umol). The reaction mixture was stirred at 80°C for 1 hr. The mixture was filtered and the solvent was concentrated under vacuum to give the crude product 3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-l-(4-(l-(2-(2-(2-(2-(l,3-dioxoisoindolin-2- yl)ethoxy)ethoxy)ethoxy)ethyl)-lH-pyrazol-4-yl)phenyl)urea (300 mg, crude) which was used for the next step directly without further purification. LCMS [M+H]⁺: 797.5.

Step B. Synthesis of l-(4-(l-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-lH-pyrazol-4- yl)phenyl)-3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)urea. To a mixture of 3-benzyl- l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4-(l-(2-(2-(2- (2-(l,3-dioxoisoindolin-2-yl)ethoxy)ethoxy)ethoxy)ethyl)-lH-pyrazol-4-yl)phenyl)urea (300 mg, 376.45 umol) in EtOH (5 mL) was added NH2NH2.H2O (57 mg, 1.1 mmol, 55 uL). The reaction mixture was stirred at 80°C for 12 hrs. The mixture was filtered and the solvent was concentrated under reduced pressure to give the residue which was purified by prep-HPLC (column: Xtimate C18 10m 250 mm *50mm; mobile phase: [water (0.04%NH₃H₂O + lOmM NH₄HCO₃)-ACN] ; B%: 35%-65%, 8min) to give the desired product l-(4-(l-(2-(2-(2-(2- aminoethoxy)ethoxy)ethoxy)ethyl)-lH-pyrazol-4-yl)phenyl)-3-benzyl-l-((lr,4r)-4-((5- cyanopyridin-2-yl)amino)cyclohexyl)urea, 45 mg. LCMS [M+H]⁺: 667.4. Step C. Synthesis of 3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4- (l-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethoxy)ethyl)-lH-pyrazol-4-yl)phenyl)urea. To a mixture of 1- (4-(l-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-lH-pyrazol-4-yl)phenyl)-3-benzyl-l- ((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)urea (35 mg, 52 umol) and 2-(2,6-dioxo- 3-piperidyl)-4-fluoro-isoindoline-l,3-dione (14.5 mg, 52 umol) in DMF (2 mL) was added DIPEA (20 mg, 157 umol, 27 uL). The reaction mixture was stirred at 90°C for 12 hrs. The mixture was concentrated under vacuum to give the residue which was purified by prep- HPLC column: (column: Boston Prime C18 150*30mm 5um; mobile phase: [water(0.04%NH3H2O+10mM NH4HCO3)-ACN];B%: 40%-70%,8min) to give the desired product 3-benzyl- l-((lr, 4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)- l-(4-(l -(2-(2-(2-(2- ((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethyl)- 1 H-pyrazol-4-yl)phenyl)urea, 17 mg. LCMS: m/z 462.0 [M+2H]²⁺/2. Ή NMR (400 MHz, CDCl₃) d 8.92 (br s, 1 H), 8.25 (d, 1 H), 7.78 (s, 1H), 7.76 (s, 1 H), 7.42 - 7.52 (m, 4 H), 7.25 - 7.28 (m, 2 H), 7.05 - 7.21 (m, 6 H), 6.87 (d, 1 H), 6.45 (br t, 1 H), 6.25 (d, 1 H), 5.05 (br s,

1H), 4.83 - 4.89 (m, 1 H), 4.51 - 4.59 (m, 1 H), 4.26 - 4.44 (m, 5 H), 3.83 - 3.92 (m, 2 H), 3.67 (t, 2 H), 3.56 - 3.64 (m, 8 H), 3.44 - 3.42 (m, 2 H), 2.65 - 2.85 (m, 3 H), 2.02 - 2.11 (m, 3 H), 1.93 - 1.99 (m, 2 H), 1.26 - 1.45 (m, 4 H).

The procedure set forth above in Example 2 was used to produce following compounds using appropriate starting materials. Standard protection and deprotection can be used when necessary.

Table II. Intermediates used in synthesizing Compounds 2-1 to 2-3

Scheme 3

Example 3. N-(2-((5-(4-(3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)ureido)phenyl)pyridin-2-yl)oxy)ethyl)-2-((2-(2,6-dioxopiperidin-3- yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamide

Step A. Synthesis of tert-butyl (2-((5-(4-(3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)ureido)phenyl)pyridin-2-yl)oxy)ethyl)carbamate. To a mixture of tert-butyl N- [2- [(5-bromo-2-pyridyl)oxy] ethyl] carbamate (40 mg, 126.11 umol), 3-benzyl- l-[4-[(5-cyano-2-pyridyl)amino]cyclohexyl]-l-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]urea (104 mg, 189 umol) in DMF (4 mL) was added CS2CO3 (82 mg, 252 umol), PdCl₂(Amphos)₂ (9 mg, 13 umol) and H2O (0.4 mL), and then the mixture was stirred at 100 °C for 1.5 hrs under N2 atmosphere. The mixture was diluted with saturated brine (10 mL) and extracted with ethyl acetate (20 mL *3). The combined organic layer was washed with brine (15 mL), dried over Na₂SO₄, filtered and concentrated in vacuum to give a crude product. The crude product was purified by prep-HPLC (column: Boston Prime C18 150*30mm 5um; mobile phase: [water(0.04% NH3H2O + lOmM NH₄HCO₃)-ACN]; B%: 55%-85%, 8min) to give the desired product tert-butyl (2-((5-(4-(3-benzyl-l-((lr,4r)-4-((5- cyanopyridin-2-yl)amino)cyclohexyl)ureido)phenyl)pyridin-2-yl)oxy)ethyl)carbamate, 55 mg. LCMS [M+H]⁺: 662.4.

Step B. Synthesis of l-(4-(6-(2-aminoethoxy)pyridin-3-yl)phenyl)-3-benzyl-l-((lr,4r)-4- ((5-cyanopyridin-2-yl)amino)cyclohexyl)urea. To a solution of tert-butyl (2-((5-(4-(3- benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)phenyl)pyridin-2- yl)oxy)ethyl)carbamate (55 mg, 83 umol) in dioxane (2 mL) was added HCl/dioxane (4 M, 1 mL). The mixture was stirred at 25 °C for 2 hrs. The solid was collected by filtration and then dried in vacuum to give the crude product which was purified again by prep-HPLC (column: Boston Prime C18 150*30mm 5um; mobile phase: [water(0.04% NH3H2O + lOmM NH₄HCO₃)-ACN] ; B%: 55%-85%, 8min) to give the desired product l-(4-(6-(2- aminoethoxy)pyridin-3-yl)phenyl)-3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)urea, 48 mg. LCMS [M+H]⁺: 562.2.

Step C. Synthesis of N-(2-((5-(4-(3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)ureido)phenyl)pyridin-2-yl)oxy)ethyl)-2-((2-(2,6-dioxopiperidin-3- yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamide. To a mixture of l-(4-(6-(2- aminoethoxy)pyridin-3-yl)phenyl)-3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)urea (42 mg, 75 umol) and 2-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo- isoindolin-4-yl]oxyacetic acid (30 mg, 90 umol) in DMF (3 mL) was added HATU (43 mg, 112 umol) and DIPEA (29 mg, 224 umol, 39 uL), then the mixture was stirred at 25 °C for 15 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with saturated NaHCO₃(15 mL) and extracted with ethyl acetate (30 mL *3). The organic layer was washed with brine (20 ml), dried over Na2SO₄, filtered and evaporated to give a crude product which was purified by prep- HPLC (column: Boston Prime C18 150*30mm 5um; mobile phase: [water (0.04% NH3H2O + lOmM NH₄HCO₃)-ACN] ; B%: 55%-85%, 8min) to give the desired product N-(2-((5-(4-(3- benzyl- l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)phenyl)pyridin-2- yl)oxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-l,3-choxoisoindolin-4-yl)oxy)acetamide, 25 mg. LCMS: m/z 438.7 [M+2H]²⁺/2. NMR (400 MHz, CDCl₃) d 8.44 - 8.18 (m, 3 H), 7.64 - 7.85 (m, 3 H), 7.37 - 7.59 (m, 4 H), 7.26 - 7.31 (m, 1 H), 7.12 - 7.24 (m, 6 H), 6.86 (d, 1 H), 6.26 (d, 1 H), 5.11 (br s, 1 H), 4.79 (dd, 1 H), 4.45 - 4.70 (m, 6 H), 4.37 (d, 2 H), 3.93 - 3.67

(m, 2 H), 3.49 (br s, 1 H), 2.45 - 2.82 (m, 3 H), 1.90 - 2.17 (m, 5 H), 1.20 - 1.49 (m, 4 H)

The procedure set forth above in Example 3 was used to produce following compounds using appropriate starting materials. Standard protection and deprotection can be used when necessary.

Table III. Intermediates used in synthesizing Compounds 3-1 to 3-14

Scheme 4

Example 4. N-(4-(2-((5-(4-(3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)ureido)phenyl)pyridin-2-yl)oxy)ethoxy)butyl)-2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamide

Step A. Synthesis of l-(4-(6-(2-(4-aminobutoxy)ethoxy)pyridin-3-yl)phenyl)-3-benzyl-l- ((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)urea. To a solution of 3-benzyl- 1- ((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)phenyl)urea (572 mg, 1 mmol), 4-[2-[(5-bromo-2- pyridyl)oxy] ethoxy] butan- 1-amine (0.3 g, 1 mmol) and Pd(dppf)Cl2.CH₂Cl2 (85 mg, 104 umol) in 1,4-dioxane (9 mL) was added NaHCO₃ (174 mg, 2 mmol) in H2O (3 mL). After the addition was completely, the reaction mixture was heated to 75°C under nitrogen and stirred at 75°C for 16hrs. EtOAc (50 mL) was added into the reaction mixture and the result mixture was washed with water (15 mL), saturated brine (15 mL), dried over Na₂SO₄, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (Dichloromethane: Methanol=20: 1 to 10:1) to give the desired product l-(4-(6-(2-(4- aminobutoxy)ethoxy)pyridin-3-yl)phenyl)-3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)urea, 0.4 g. LCMS: m/z 634.4 [M+H]⁺. ¹H NMR (400 MHz, METHANOL-^) d 8.39 - 8.42 (m, 1 H), 8.17 - 8.20 (m, 1 H), 7.98 (d, 1 H), 7.71 (d, 2 H), 7.49 (d, 1 H), 7.14 - 7.33 (m, 7 H), 6.90 (d, 1 H), 6.43 (d, 1 H), 4.38 - 4.48 (m, 3 H), 4.26 (s,

2 H), 3.76 - 3.83 (m, 2 H), 3.56 (t, 3 H), 2.70 (t, 2 H), 1.98 - 2.09 (m, 2 H), 1.94 (br d, 2 H), 1.53 - 1.69 (m, 4 H), 1.24 - 1.47 (m, 4 H).

Step B. Synthesis of N-(4-(2-((5-(4-(3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)ureido)phenyl)pyridin-2-yl)oxy)ethoxy)butyl)-2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamide. To a solution of l-(4-(6-(2- (4-aminobutoxy)ethoxy)pyridin-3-yl)phenyl)-3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)urea (0.1 g, 158 umol), 2-((2-(2,6 -dioxopiperidin-3-yl)-l,3- dioxoisoindolin-4-yl)oxy)acetic acid (52 mg, 158 umol) and DIPEA (31 mg, 237 umol) in DMSO (0.5 mL) was added HATU (90 mg, 237 umol). After the addition was completely, the reaction mixture was stirred at 25 °C for 16hrs. The solution was purified by prep-HPLC (Prep_HPLC: column: Phenomenex Gemini-NX 150*30mm*5um; mobile phase: [water(0.04% NH₃H₂O+10mM NH₄HCO₃)-ACN]; B%: 44%-74%, 8min.) directly to give the desired product N-(4-(2-((5-(4-(3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)ureido)phenyl)pyridin-2-yl)oxy)ethoxy)butyl)-2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamide, 40 mg. LCMS: m/z 474.8

11.08 (br s, 1 H), 8.53 (d, 1 H), 8.29 (d, 1 H), 8.06 (dd, 1 H), 7.97 (br t, 1 H), 7.73 - 7.84 (m, 3 H), 7.61 (dd, 1 H), 7.49 (d, 2 H), 7.40 (d, 1 H), 7.24 - 7.32 (m, 4 H), 7.16 - 7.22 (m, 3 H), 6.94 (d, 1 H), 6.48 (d, 1 H), 5.91 (br t, 1 H), 5.12 (dd, 1 H), 4.78 (s, 2 H), 4.38 - 4.47 (m, 2 H), 4.25 - 4.37 (m, 1 H), 4.17 (br d, 2 H), 3.66 - 3.78 (m, 2 H), 3.42 - 3.52 (m, 2 H), 3.27 - 3.33 (m, 2 H), 3.12 - 3.25 (m, 2 H), 2.83 - 2.98 (m, 1 H), 2.63 - 2.36 (m, 2 H), 2.00 - 2.08 (m, 1 H), 1.93 (br d, 2 H), 1.84 (br d, 2 H), 1.44 - 1.59 (m, 4 H), 1.29 - 1.39 (m, 2 H), 1.11 - 1.23 (m, 2 H).

The procedure set forth above in Example 4 was used to produce following compounds using appropriate starting materials. Standard protection and deprotection can be used when necessary.

Table IV. Intermediates used in synthesizing Compounds 4-1 to 4-6

Scheme 5

Example 5. (2S,4R)-l-((S)-2-(2-(2-(4-((3-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-3-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ureido)methyl)-lH-pyrazol-l-yl)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

Step A. Synthesis of ethyl 2-(2-(4-((3-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)- 3-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)ureido)methyl)-lH-pyrazol-l- yl)ethoxy)acetate. To a solution of 3-((lH-pyrazol-4-yl)methyl)-l-((lr,4r)-4-((5- cyanopyridin-2-yl)amino)cyclohexyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)urea (100 mg, 191 umol) in DMF (5 mL) was added CS2CO3 (125 mg, 383 umol) and ethyl 2-[2-(p-tolylsulfonyloxy)ethoxy]acetate (58 mg, 191 umol). The mixture was stirred at 80 °C for 1.5hrs. The reaction mixture was diluted with H2O (15 mL), The solid was collected by filtration and then dried in vacuum to give desired product ethyl 2-(2-(4-((3- ((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(l-methyl-6-oxo-l,6- dihydropyridin-3-yl)phenyl)ureido)methyl)-lH-pyrazol-l-yl)ethoxy)acetate, 70 mg, crude. LCMS [M+H]⁺: 653.4.

Step B. Synthesis of 2-(2-(4-((3-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4- (l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)ureido)methyl)-lH-pyrazol-l- yl)ethoxy)acetic acid. To a solution of ethyl 2-(2-(4-((3-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-3-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)ureido)methyl)- lH-pyrazol-l-yl)ethoxy)acetate (70 mg, 107.24 umol) in THF (4 mL) was added LiOH.FbO (5 mg, 118 umol) and H2O (1 mL). The mixture was stirred at 25 °C for 2 hrs. The reaction mixture was cooled to 0°C and adjusted to pH = 6 with HC1 (1 M) solution. The resulting mixture was lyophilized in vacuum to give a crude product 2-(2-(4-((3-((lr,4r)-4-((5- cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ureido)methyl)-lH-pyrazol-l-yl)ethoxy)acetic acid, 70 mg, 80% purity. LCMS [M+H]⁺: 625.3.

Step C. Synthesis of (2S,4R)-l-((S)-2-(2-(2-(4-((3-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-3-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ureido)methyl)-lH-pyrazol-l-yl)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4- hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide. To a solution of 2-(2-(4-((3-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(l-methyl-6-oxo-l,6- dihydropyridin-3-yl)phenyl)ureido)methyl)-lH-pyrazol-l-yl)ethoxy)acetic acid (70 mg, 112.06 umol) and (2S,4R)-l-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4- methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (48 mg, 112 umol) in DMF (4 mL) was added HATU (64 mg, 168 umol) and TEA (34 mg, 336 umol). The mixture was stirred at 25 °C for 15 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with saturated NaHCCL (15 mL) and extracted with ethyl acetate (30 mL *3). The organic layer was washed with brine (20 ml), dried over Na₂SO₄, filtered and evaporated to give a crude product. The crude product was purified by prep-HPLC(column: Boston Green ODS 150*305u; mobile phase: [water (0.04% N¾ HiO + 10 mM NH₄HCO₃)-ACN]; B%: 25%-55%, 8min) to give the desired product (2S,4R)- l-((S)-2-(2-(2-(4-((3-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(l-methyl-6- oxo-l,6-dihydropyridin-3-yl)phenyl)ureido)methyl)-lH-pyrazol-l-yl)ethoxy)acetamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, 28 mg. NMR(400 MHz, CDCl₃) d 8.68 (s, 1 H), 8.27 (d, 1 H), 7.86 (br t, 1 H), 7.60 (dd, 1 H), 7.52 (d, 1H), 7.29 - 7.49 (m, 9 H), 7.18 (d, 1 H), 7.09 (d, 2 H), 6.69 (d, 1 H), 6.26 (d, 1 H), 4.92 (br s, 1 H), 4.69 - 4.80 (m, 1 H), 4.50 - 4.67 (m, 3 H), 4.36 - 4.48 (m, 2 H), 4.17 - 4.32 (m, 4 H), 4.00 - 4.09 (m, 1 H), 3.91 - 3.98 (m, 2 H), 3.82 - 3.89 (m, 1 H), 3.61 - 3.76 (m,

6 H), 3.51 (br d, 1 H), 2.39 - 2.57 (m,5 H), 2.01 - 2.28 (m, 4 H), 1.79 - 1.97 (m, 3 H), 1.10 - 1.48 (m, 4 H), 0.77 - 1.02 (m, 9 H); LCMS [M+2H]²⁺/2: 519.3

The procedure set forth above in Example 5 was used to produce following compounds using appropriate starting materials. Standard protection and deprotection can be used when necessary.

Table V. Intermediates used in synthesizing Compounds 5-9, 5-14, and 5-15

Scheme 6

L = R¹ or 0-R¹as defined in Formula (I);

Example 6. N-(2-((4-(4-(3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)ureido)phenyl)pyridin-2-yl)oxy)ethyl)-2-((2-(2,6-dioxopiperidin-3- yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamide

Step A. Synthesis of tert-butyl (2-((4-bromopyridin-2-yl)oxy)ethyl)carbamate. To a solution of tert-butyl N-(2-hydroxyethyl)carbamate (1.83 g, 11.36 mmol, 1.76 mL) and 4- bromo-2-fluoro-pyridine (1 g, 5.68 mmol) in THF (10 mL) was added NaH (341 mg, 8.52 mmol, 60% purity) under nitrogen at 0°C. After the addition was completely, the reaction mixture was allowed to warm up to 25 °C and stirred at 25 °C for 16hrs. The reaction mixture was cooled to 0°C and quenched by saturated NH4CI (25 mL). The result mixture was extracted with EtOAc (4 x 15 mL). The combined organic layer was washed with saturated brine (30 mL), dried over Na₂SO₄, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (Petroleum ether: Ethyl acetate =20: 1 to 1:1) to give the desired product tert-butyl (2-((4-bromopyridin-2-yl)oxy)ethyl)carbamate, 1.1

7.96 (d, 1 H), 7.04 (d, 1 H), 6.95 (s, 1 H), 4.97 (br s, 1 H), 4.35 (t, 2 H), 3.52 (q, 2 H), 1.44 (s, 9 H)

Step B. Synthesis of tert-butyl (2-((4-(4-(3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)ureido)phenyl)pyridin-2-yl)oxy)ethyl)carbamate. To a solution of 3- benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4-(4, 4,5, 5-tetramethyl- 1,3,2- dioxaborolan-2-yl)phenyl)urea (348 mg, 630 umol), tert-butyl (2-((4-bromopyridin-2- yl)oxy)ethyl)carbamate (0.2 g, 631 umol) and Pd(dppf)Cl2.CH₂Cl2 (51 mg, 63 umol) in 1,4- dioxane (9 mL) was added NaHCCL (1060 mg, 1.3 mmol) in H2O (3 mL). After the addition was completely, the reaction mixture was heated to 75°C under nitrogen and stirred at 75°C for 16hrs. EtOAc (50 mL) was added into the reaction mixture and the result mixture was washed with water (15 mL) and saturated brine (15 mL), dried over Na₂SO₄, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (Petroleum ether: Ethyl acetate=20:l to 1:1) to give 0.3 g desired product tert-butyl (2-((4-(4- (3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)phenyl)pyridin-2- yl)oxy)ethyl)carbamate. LCMS: m/z 662.3 [M+H]⁺.

Step C. Synthesis of l-(4-(2-(2-aminoethoxy)pyridin-4-yl)phenyl)-3-benzyl-l-((lr,4r)-4- ((5-cyanopyridin-2-yl)amino)cyclohexyl)urea. To a solution of tert-butyl (2-((4-(4-(3- benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)phenyl)pyridin-2- yl)oxy)ethyl)carbamate (0.2 g, 302 umol) in 1,4-dioxane (1 mL) was added HCl/dioxane (4 M, 1 mL). After the addition was completely, the reaction mixture was stirred at 20°C for lhr.The reaction mixture was basified by saturated NaHCO₃ to (pH~8) and the resulting mixture was extracted with DCM: MeOH = 10:1 (4 x 20 mL). The combined organic lays were washed with saturated brine (30 mL), dried over Na₂SO₄, filtered and concentrated to dry. The residue was purified by column chromatography on silica gel (Petroleum ether:

Ethyl acetate=20:l to 10:1) to give 0.15 g desired product l-(4-(2-(2-aminoethoxy)pyridin-4- yl)phenyl)-3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)urea. LCMS: m/z 562.3

8.15 - 8.20 (m, 2 H), 7.82 (m, 2 H), 7.48 (d, 1 H), 7.34 (m, 2 H), 7.12-7.28 (m, 7 H), 6.43 (d, 1 H), 4.30 - 4.46 (m, 3 H), 4.26 (s, 2 H), 3.44 - 3.64 (m, 1 H), 3.03 (t, 2 H), 2.02 (br d, 2 H), 1.94 (br d, 2 H), 1.24 - 1.46 (m, 4 H). Step D. Synthesis of N-(2-((4-(4-(3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)ureido)phenyl)pyridin-2-yl)oxy)ethyl)-2-((2-(2,6-dioxopiperidin-3- yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamide. To a solution of l-(4-(2-(2- aminoethoxy)pyridin-4-yl)phenyl)-3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)urea (0.125 g, 223 umol), 2-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-4-yl)oxy)acetic acid (74 mg, 223 umol) and DIPEA (43 mg, 334 umol, 58 uL) in DML (2 mL) was added HATU (127 mg, 334 umol). After the addition was completely, the reaction mixture was stirred at 25 °C for 16hrs. The solution was further work-up and purified by prep-HPLC (Prep-HPLC: column: Phenomenex Gemini-NX 150*30mm*5um; mobile phase: [water (0.04%NH₃ H₂O + 10mM NH₄HCO₃)-ACN; B%: 40%-70%, 8min.] directly to give 95 mg desired product N-(2-((4-(4-(3-benzyl-l-((lr,4r)-4- ((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)phenyl)pyridin-2-yl)oxy)ethyl)-2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamide. LCMS: m/z 876.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) d 8.26 (s, 1 H), 8.17 (br d, 1 H), 8.06 (br s, 1 H), 7.83 (br s, 1 H), 7.61 - 7.72 (m, 3 H), 7.48 (br d, 1 H), 7.44 (br d, 1 H), 7.15 - 7.30 (m, 8 H), 7.07 (br d, 1 H), 6.95 (s, 1 H), 6.26 (br d, 1 H), 5.00 (br s, 1 H), 4.64 - 4.71 (m, 3 H), 4.49 - 4.64 (m, 4 H), 4.29 - 4.43 (m, 2 H), 3.80 (br s, 2 H), 3.51 (br s, 1 H), 2.52 - 2.68 (m, 2 H), 2.34 - 2.44 (m, 1 H), 2.10 (br d, 2 H), 1.89 - 2.04 (m, 3 H), 1.22 - 1.46 (m, 4 H).

The procedure set forth above in Example 6 was used to produce following compounds using appropriate starting materials. Standard protection and deprotection can be used when necessary.

Scheme 7

Example 7. N-(3-(2-(2-((4-(4-(3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)ureido)phenyl)pyridin-2-yl)oxy)ethoxy)ethoxy)propyl)-2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamide

Step A. Synthesis of 3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4- (2-fluoropyridin-4-yl)phenyl)urea. A mixture of 3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)urea (4 g, 7.25 mmol), 4-bromo-2-fluoro-pyridine (1.40 g, 7.98 mmol), Pd(dppf)Cl2 (530 mg, 725 umol) and Na₂CO₃ (2.31 g, 21.76 mmol) in H2O (20 mL) and dioxane (40 mL) was stirred at 100 °C for 2 hrs under N2. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL * 3). The combined organic layers were washed with saturated NaCl (30 mL * 2), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂,

Petroleum ether/Ethyl acetate=0/l to 1/3) to give the desired product 3-benzyl-l-((lr,4r)-4- ((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4-(2-fluoropyridin-4-yl)phenyl)urea, 3.7 g. LCMS: m/z 521.3 [M+H]⁺ Step B. Synthesis of tert-butyl (3-(2-(2-((4-(4-(3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)ureido)phenyl)pyridin-2-yl)oxy)ethoxy)ethoxy)propyl)carbamate.

To a mixture of tert-butyl N-[3-[2-(2-hydroxyethoxy)ethoxy]propyl]carbamate (121 mg, 461 umol) in THF (6 mL) was added NaH (61 mg, 1.54 mmol, 60% purity). The mixture was stirred at 25°C for 20 min. Then 3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-l-(4-(2-fluoropyridin-4-yl)phenyl)urea (200 mg, 384 umol) was added to the reaction mixture. The reaction mixture was stirred at 40°C for 2 hrs. The mixture was quenched by addition saturated NFLCl (15 mL) and extracted with ethyl acetate (15 mL * 3). The organic layers were dried Na₂SO₄, filtered and the solvent was concentrated under reduced pressure to give the desired product tert-butyl (3-(2-(2-((4-(4-(3-benzyl-l-((lr,4r)-4- ((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)phenyl)pyridin-2- yl)oxy)ethoxy)ethoxy)propyl)carbamate (350 mg, crude) which was used for the next step directly without further purification. LCMS: m/z 764.4 [M+H]⁺

Step C. Synthesis of l-(4-(2-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)pyridin-4-yl)phenyl)- 3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)urea. To a mixture of tert- butyl (3-(2-(2-((4-(4-(3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)ureido)phenyl)pyridin-2-yl)oxy)ethoxy)ethoxy)propyl)carbamate (250 mg, 327 umol) in DCM (8 mL) was added HCl/dioxane (4 M, 2 mL). The reaction mixture was stirred at 25°C for 1 hr. The mixture was concentrated under reduced pressure to give the desired product l-(4-(2-(2-(2-(3-aminopropoxy)ethoxy)ethoxy)pyridin-4-yl)phenyl)-3- benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)urea (220 mg, crude, HC1 salt). LCMS: m/z 664.4 [M+H]⁺

Step D. Synthesis of N-(3-(2-(2-((4-(4-(3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)ureido)phenyl)pyridin-2-yl)oxy)ethoxy)ethoxy)propyl)-2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamide. To a mixture of l-(4-(2-(2- (2-(3-aminopropoxy)ethoxy)ethoxy)pyridin-4-yl)phenyl)-3-benzyl-l-((lr,4r)-4-((5- cyanopyridin-2-yl)amino)cyclohexyl)urea (200 mg, 173 umol, HC1 salt) and 2-[2-(2,6-dioxo- 3-piperidyl)-l,3-dioxo-isoindolin-4-yl]oxyacetic acid (58 mg, 173 umol) in DMF (3 mL) were added HATU (99 mg, 260 umol) and Et3N (53 mg, 520 umol). The reaction mixture was stirred at 25 °C for 1 hr. The mixture was filtered and the solvent was concentrated under reduced pressure to give the residue. The residue was purified by prep- HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water (0.04%NH₃H₂O + 10mM NH₄HCO₃)-ACN]; B%: 44%-74%, 8min) to give the desired product N-(3-(2-(2-((4- (4-(3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)ureido)phenyl)pyridin-2- yl)oxy)ethoxy)ethoxy)propyl)-2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)acetamide, 56 mg. LCMS: m/z 489.8 [M+2H]²⁺/2. 1H NM R (400 MHz, CDCl₃) d 8.73 (br s, 1 H), 8.26 (d, 1 H), 8.18 (d, 1 H), 7.69 - 7.74 (m, 1 H), 7.63 (d, 2 H), 7.50 - 7.56 (m, 2 H), 7.45 (dd, 1 H), 7.26 - 7.29 (m, 2 H), 7.15 - 7.22 (m, 4 H), 7.06 (dd, 1 H), 6.96 (s, 1 H), 6.26 (d, 1 H), 4.90 (br dd, 2 H), 4.49 - 4.66 (m, 5 H), 4.36 (s, 3 H), 3.88 (dd, 2 H), 3.69 - 3.73 (m, 2 H), 3.60 - 3.64 (m, 2 H), 3.56 (br t, 2 H), 3.38 - 3.51 (m, 3 H), 2.63 - 2.90 (m, 3 H),

2.06 - 2.15 (m, 3 H), 1.98 (br d, 2 H), 1.85 (quin, 2 H), 1.27 - 1.44 (m, 4 H). The procedure set forth above in Example 7 was used to produce following compounds using appropriate starting materials. Standard protection and deprotection can be used when necessary.

Table VI. Intermediates used in synthesizing Compounds 7-2 to 7-16

Example 8. N-(4-(4-((3-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(l- methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)ureido)methyl)phenoxy)butyl)-2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamide

Step A. Synthesis of tert-butyl (4-(4-((3-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-3-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ureido)methyl)phenoxy)butyl)carbamate. To a mixture of l-((lr,4r)-4-((5- cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-hydroxybenzyl)-l-(4-(l-methyl-6-oxo-l,6- dihydropyridin-3-yl)phenyl)urea (200 mg, 365 umol) and tert-butyl N-(4- hydroxybutyl)carbamate (83 mg, 437 umol) in THF (10 mL) was added PPh3 (286.85 mg, 1.09 mmol) and DBAD (251.82 mg, 1.09 mmol) at 0 °C. The reaction mixture was stirred at 30°C for 12 hrs. The mixture was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO₂, Dichloromethane : Methanol=10:0 to 10:1) to give the desired product tert-butyl (4-(4-((3-((lr,4r)-4-((5- cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ureido)methyl)phenoxy)butyl)carbamate (80 mg, 73% purity). LCMS: m/z 720.5 [M+H]⁺

Step B. Synthesis of 3-(4-(4-aminobutoxy)benzyl)-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea. To a solution of tert-butyl (4-(4-((3-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(l- methyl-6-oxo- 1 ,6-dihydropyridin-3-yl)phenyl)ureido)methyl)phenoxy)butyl)carbamate (80 mg, 111 umol) in MeOH (1 mL) was added HCl/MeOH (4 M, 1 mL). The reaction mixture was stirred at 25°C for 1 hr. The mixture was concentrated under reduced pressure to give the desired product 3-(4-(4-aminobutoxy)benzyl)-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea (70 mg, HC1 salt, crude) which was used for the next step directly without further purification.

Step C. Synthesis of N-(4-(4-((3-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3- (4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)ureido)methyl)phenoxy)butyl)-2-((2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamide. To a mixture of 3-(4-(4- aminobutoxy)benzyl)-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4-(l -methyl- 6-oxo- l,6-dihydropyridin-3-yl)phenyl)urea (70 mg, 78 umol, HC1 salt) and2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetic acid (28 mg, 86 umol) in DMF (3 mL) was added HATU (44 mg, 117 umol) and DIPEA (30 mg, 233 umol). The reaction mixture was stirred at 25 °C for 1 hr. The mixture was filtered and the solvent was concentrated under reduced pressure to give the residue. The residue was purified by prep- HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: [water(0.04%NH₃H₂O + lOmM NH₄HCO3)-ACN]; B%: 35%-65%, 8min) to give the desired product N-(4-(4-((3- ((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(l-methyl-6-oxo-l,6- dihydropyridin-3-yl)phenyl)ureido)methyl)phenoxy)butyl)-2-((2-(2,6-dioxopiperidin-3-yl)- l,3-dioxoisoindolin-4-yl)oxy)acetamide (42 mg). LCMS: m/z 467.8 [M+2H]²⁺/2. ¹ H NMR (400 MHz, CDCl₃) d 8.44 (s, 1 H), 8.26 (d, Hz, 1 H), 7.73 (dd, 1 H), 7.59 (dd, 1 H), 7.40 - 7.55 (m, 6 H), 7.15 - 7.21 (m, 3 H), 7.05 (d, 2 H), 6.77 (d, 2 H), 6.68 (d, 1 H), 6.26 (d, 1 H), 4.80 - 4.91 (m, 2 H), 4.61 (s, 2 H), 4.54 - 4.60 (m, 1 H), 4.26 (s, 3 H), 3.94 (t, 2 H), 3.62 (s, 3 H), 3.40 -3.54 (m, 3 H), 2.61 - 2.84 (m, 3 H), 2.02 - 2.11 (m, 3 H), 1.97 (br d, 2 H), 1.72 - 1.88 (m, 4 H), 1.22 - 1.43 (m, 4 H)

The procedure set forth above in Example 8 was used to produce following compounds using appropriate starting materials. Standard protection and deprotection can be used when necessary.

Scheme 9

Example 9. N-(3-(4-((3-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(l- methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)ureido)methyl)phenoxy)propyl)-2-((2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamide

Step A. Synthesis of tert-butyl (3-(4-((3-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-3-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ureido)methyl)phenoxy)propyl)carbamate. To a solution of l-((lr,4r)-4-((5- cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-hydroxybenzyl)-l-(4-(l-methyl-6-oxo-l,6- dihydropyridin-3-yl)phenyl)urea (0.15 g, 273 umol) and tert-butyl N-(3- bromopropyl)carbamate (98 mg, 410 umol)in DMF (2 mL) was added CS2CO3 (178 mg, 547 umol). After the addition was complete, the reaction mixture was stirred at 90°C for 16 hrs. Water (25 mL) was added into the result mixture and the resulting mixture was extracted with EtOAc (4 x 15 mL). The combined organic layer was washed with brine (25 mL), dried over Na₂SO₄, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (Dichloromethane : Methanol=50: 1 to 20:1) to give the desired product Synthesis of tert-butyl (3-(4-((3-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)- 3-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ureido)methyl)phenoxy)propyl)carbamate (152 mg). LCMS: m/z 706.4 [M+H]⁺.

Step B. 3-(4-(3-aminopropoxy)benzyl)-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea. To a solution of tert-butyl (3-(4-((3-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(l- methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)ureido)methyl)phenoxy)propyl)carbamate (0.15 g, 212.51 umol) in DCM (2 mL) was added HC1 (4 M, 2.14 mL). After the addition was complete, the reaction mixture was stirred at 20°C for lhrs. The reaction mixture was basified by saturated NaHCO₃ (pH~8). The result mixture was extracted with EtOAc (4 x 25 mL). The combined organic layer was washed with saturated brine (30 mL), dried over Na₂SO₄, filtered and concentrated to dryness to give the desired product 3-(4-(3- aminopropoxy)benzyl)-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4-(l- methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea (0.15 g crude) which was used for the next step directly without further purification. LCMS: m/z 606.3 [M+H]⁺.

Step C. N-(3-(4-((3-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(l-methyl- 6-oxo-l,6-dihydropyridin-3-yl)phenyl)ureido)methyl)phenoxy)propyl)-2-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamide. To a solution of 3-(4-(3- aminopropoxy)benzyl)-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4-(l- methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea (0.1 g, 156 umol, HC1), 2-[2-(2,6-dioxo- 3-piperidyl)-l,3-dioxo-isoindolin-4-yl]oxyacetic acid (52 mg, 156 umol) and DIPEA (30 mg, 234 umol, 41 uL) in DML (2 mL) was added HATU (89 mg, 234 umol). After the addition was complete, the reaction mixture was stirred at 20°C for 16 hrs. The reaction mixture was filtered and the filtrate was purified by prep-HPLC, Prep-HPLC: column: Boston Prime C18 150*30mm*5um; mobile phase: [water(0.04% NH3H2O + lOmM NH₄HCO₃)-ACN];

B %: 35%-65%, 8min. to give the desired product N-(3-(4-((3-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-3-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ureido)methyl)phenoxy)propyl)-2-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-4-yl)oxy)acetamide (75 mg). LCMS: m/z 460.8 [M+2H]²⁺/2. ¹ H NMR (400 MHz, DMSO-d6) d 11.08 (br s, 1 H), 8.25 (d, 1 H), 8.14 (d, 1 H), 8.03 (t, 1 H), 7.82 (dd, 1 H), 7.72 (dd, 1 H), 7.60 (d, 2 H), 7.56 (dd, 1 H), 7.44 (d, 2 H), 7.34 (d, 1 H), 7.16 (d, 2 H), 7.05 (d, 2 H), 6.77 (d, 2 H), 6.46 (d, 1 H), 6.42 (d, 1 H), 5.69 (br t, 1 H), 5.07 (dd, 1 H), 4.74 (s, 2 H), 4.25 (br t, 1 H), 4.04 (br d, 2 H), 3.90 (t, 2 H), 3.48 (s, 3 H), 3.23 - 3.28 (m, 2 H), 2.80 - 2.90 (m, 1 H), 2.49 - 2.58 (m, 2 H), 1.93 - 2.04 (m, 1 H), 1.73 - 1.93 (m, 6 H), 1.18 - 1.38 (m, 2 H), 1.01 - 1.18 (m, 2 H)

The procedure set forth above in Example 9 was used to produce following compounds using appropriate starting materials. Standard protection and deprotection can be used when necessary.

Table VII. Intermediates used in synthesizing Compounds 9-3 to 9-12

Scheme 10

Example 10. 3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4-(6-(2- ((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)ethyl)pyridin-3-yl)phenyl)urea

Step A. Synthesis of 3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4- (6-(2-hydroxyethyl)pyridin-3-yl)phenyl)urea. To a solution of 3-benzyl-l-((lr,4r)-4-((5- cyanopyridin-2-yl)amino)cyclohexyl)-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)urea (0.5 g, 906 umol), 2-(5-bromo-2-pyridyl)ethanol (183 mg, 907 umol) and Pd(dppf)Cl2.DCM (74 mg, 91 umol) in 1,4-dioxane (6 mL) was added NaHCO₃ (152 mg, 1.81 mmol) in H₂O (2 mL). After the addition was completely, the reaction mixture was heated to 75°C under nitrogen and stirred at 75°C for 16 hrs. EtOAc (50 mL) was added into the result mixture and the result mixture was washed with water (15 mL), saturated brine (15 mL), dried over Na₂SO₄, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (Petroleum ether : Ethyl acetate=10 to 0:1) to give the desired product Synthesis of 3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)- l-(4-(6-(2-hydroxyethyl)pyridin-3-yl)phenyl)urea (0.25 g).

Step B. 3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4-(6-(2-((2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)ethyl)pyridin-3-yl)phenyl)urea.

To a solution of 3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4-(6-(2- hydroxyethyl)pyridin-3-yl)phenyl)urea (0.1 g, 182.93 umol), 2-(2,6-dioxo-3-piperidyl)-4- hydroxy-isoindoline-l,3-dione (50 mg, 183 umol) and DIAD (111 mg, 549 umol) in THF (1 mL) was added PPh ₃ (144 mg, 549 umol). After the addition was complete, the reaction mixture was stirred at 30°C for 16 hrs. DCM (50 mL) was added into the result mixture and the result mixture was washed with water (15 mL), brine (15 mL), dried over Na₂SO₄, filtered and concentrated to dryness. The residue was purified by prep-HPLC: Prep-HPLC: column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (lOmM NH4HCO3)- ACN]; B%: 27%-57%, 30min. to give the desired product 3-benzyl-l-((lr,4r)-4-((5- cyanopyridin-2-yl)amino)cyclohexyl)-l-(4-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-4-yl)oxy)ethyl)pyridin-3-yl)phenyl)urea (45 mg). LCMS: m/z 402.2,

11.12 (s, 1 H), 8.89 (d, 1 H), 8.29 (d, 1 H), 8.09 (dd, 1 H), 7.79 - 7.88 (m, 3 H), 7.55 - 7.68 (m, 3 H), 7.44 - 7.54 (m, 2 H), 7.25 - 7.34 (m, 4 H), 7.16 - 7.22 (m, 3 H), 6.47 (d, 1 H), 5.97 (br t, 1 H), 5.08 (dd, 1 H), 4.64 (t, 2 H), 4.28 - 4.37 (m, 1 H), 4.17 (br d, 2 H), 3.26 - 3.33 (m, 2 H), 2.83 - 2.93 (m, 1 H), 2.53 - 2.61 (m, 2

H), 1.89 - 2.13 (m, 3 H), 1.85 (br d, 2 H), 1.25 - 1.41 (m, 2 H), 1.06 - 1.25 (m, 2 H)

The procedure set forth above in Example 10 was used to produce following compounds using appropriate starting materials. Standard protection and deprotection can be used when necessary

Scheme 11

Example 11. 3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4-(6-(2- ((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)ethoxy)pyridin-3- yl)phenyl)urea

Step A. Synthesis of 3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4- (6-fluoropyridin-3-yl)phenyl)urea. To a solution of 3-benzyl-l-[4-(4- cyanoanilino)cyclohexyl]-l-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]urea (2 g, 3.63 mmol) in dioxane (20 mL) and H₂O (10 mL) was added 5-bromo-2-fluoro-pyridine (703 mg, 4.00 mmol), Pd(dppf)Cl2 (266 mg, 363 umol) and Na₂CO₃ (1.16 g, 10.90 mmol). The mixture was stirred at 100 °C for 2 hrs. The reaction mixture was diluted with H2O (100 mL) and extracted with DCM (100 mL*3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/l to 1/100) give the desired product 3-benzyl- l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)- 1-(4-(6- fluoropyridin-3-yl)phenyl)urea (1.6 g) . ¹H NMR (400 MHz, CDCI3) d 8.44 (d, 1 H), 8.28 (d,

1 H), 7.98 (td, 1 H), 7.54 - 7.66 (m, 2 H), 7.35 - 7.53 (m, 2 H), 7.18 - 7.33 (m, 6 H), 7.06 (dd, 1 H), 6.28 (d, 1 H), 4.89 (br d, 1 H), 4.55 - 4.69 (m, 1 H), 4.28 - 4.46 (m, 3 H), 3.55 (br s, 1 H), 2.13 (br d, 2 H), 2.02 (br d, 2 H), 1.24 - 1.49 (m, 4 H).

Step B. Synthesis of 3-benzyl-l-((lr, 4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4- (6-(2-hydroxyethoxy)pyridin-3-yl)phenyl)urea. To a solution of 3-benzyl-l-((lr,4r)-4-((5- cyanopyridin-2-yl)amino)cyclohexyl)-l-(4-(6-fluoropyridin-3-yl)phenyl)urea (200 mg, 385 umol) in DMF (2 mL) was added ethylene glycol (239 mg, 3.85 mmol), NaH (62 mg, 1.54 mmol, 60% purity) at 0°C, and the mixture was stirred at 40°C for 12 hrs. The reaction mixture was quenched by addition H2O (10 mL) at 0°C, and extracted with DCM (20 mL*3). The combined organic layers were concentrated under reduced pressure to give the crude product 3-benzyl- l-((lr, 4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4-(6-(2- hydroxyethoxy)pyridin-3-yl)phenyl)urea (314 mg, crude). LCMS [M+H]⁺: 563.4.

Step C. Synthesis of 3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4- (6-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)ethoxy)pyridin-3- yl)phenyl)urea. To a solution of 3-benzyl-l-((lr, 4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-l-(4-(6-(2-hydroxyethoxy)pyridin-3-yl)phenyl)urea (270 mg, 480 umol) in THF (3 mL) was added 2-(2,6-dioxo-3-piperidyl)-4-hydroxy-isoindoline-l,3-dione (132 mg, 480 umol), PPh3 (252 mg, 960 umol) and DIAD (194 mg, 960 umol) at 0°C, then the mixture was stirred at 20°C for 12 hrs. The reaction mixture was submitted to prep_HPLC purification directly without any work-up (column: Boston Prime C18 150*30mm*5um;mobile phase: [water (0.04%NH₃H²O + lOmM NH₄HCO₃)-ACN]; B%: 50%-80%,8min) to give the desired product 3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-l-(4-(6-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)ethoxy)pyridin-3-yl)phenyl)urea. (43 mg). ¹ H NMR (400 MHz, METHANOL-iL) d 8.40 (d, 1 H), 8.18 (d, 1 H), 7.96 (dd, 1 H), 7.81 (dd, 1 H), 7.70 (d, 2 H), 7.42 - 7.53 (m, 3 H), 7.12 - 7.33 (m, 7 H), 6.88 (d, 1 H), 6.43 (d, 1 H), 5.04 (dd, 1 H), 4.72 - 4.79 (m, 2 H), 4.58 - 4.64 (m, 4 H), 4.42 (br t, 1 H), 4.27 (s, 2 H), 3.53 (br s, 1 H), 2.58 - 2.87 (m, 3 H), 1.98 - 2.09 (m, 3 H), 1.93 (br d, 2 H), 1.23 - 1.43 (m, 4 H); LCMS [M+H]⁺: 819.3.

The procedure set forth above in Example 11 was used to produce following compounds using appropriate starting materials. Standard protection and deprotection can be used when necessary

Scheme 12

Example 12. l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(4-((2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)butoxy)benzyl)-l-(4-(l-methyl-6-oxo- l,6-dihydropyridin-3-yl)phenyl)urea

Step A. Synthesis of 3-(4-(4-((tert-butyldimethylsilyl)oxy)butoxy)benzyl)-l-((lr,4r)-4- ((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)urea. To a solution of l-[4-[(5-cyano-2-pyridyl)amino]cyclohexyl]-3-[(4- hydroxyphenyl)methyl]-l-[4-(l-methyl-6-oxo-3-pyridyl)phenyl]urea (300 mg, 547 umol) in DMF (5 mL) was added CS2CO3 (356 mg, 1.09 mmol) and 4-bromobutoxy-tert- butyl-dimethyl-silane (219.23 mg, 820.22 umol). The mixture was stirred at 60 °C for 15 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The mixture was diluted with saturated brine (15 ruL) and extracted with DCM (30 ruL *3). The organic layer was washed with brine (20 ml), dried over Na₂SO₄, filtered and evaporated to give a crude product. The crude product was purified by column chromatography (S1O2, DCM: MeOH=l/0 to 20/1) to give a the desired compound 3-(4-(4-((tert- butyldimethylsilyl)oxy)butoxy)benzyl)-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea (360 mg). LCMS [M+H]⁺: 735.4.

Step B. Synthesis of l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(4- hydroxybutoxy)benzyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea. To a solution of 3-(4-(4-((tert-butyldimethylsilyl)oxy)butoxy)benzyl)-l-((lr,4r)-4-((5- cyanopyridin-2-yl)amino)cyclohexyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)urea (280 mg, 381 umol) in THF (2 ruL) was added TBAF (1 M in THF, 762 uL). The mixture was stirred at 25 °C for 15 hrs. The mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (S1O2, Dichloromethane : Methanol=l:0 to 50/1) to give the desired compound l-((lr,4r)-4- ((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(4-hydroxybutoxy)benzyl)-l-(4-(l-methyl-6- oxo-l,6-dihydropyridin-3-yl)phenyl)urea (100 mg,). LCMS [M+H]⁺: 621.4. ¹ H NMR(400 MHz, CDCI3) d 8.25 (d, 1 H), 7.56 - 7.64 (m, 1 H), 7.50 (d, 1 H), 7.40 - 7.45 (m, 3 H), 7.18 (d, 2 H), 7.08 (d, 2 H), 6.78 (d, 2 H), 6.67 (d, 1 H), 6.26 (d, 1 H), 5.04 (br d, 1 H), 4.52 - 4.69 (m, 1 H), 4.14 - 4.35 (m, 3 H), 3.94 (t, 2 H), 3.66 - 3.73 (m, 2 H), 3.62 (s, 3 H), 3.49 - 3.57 (m, 1 H), 2.09 (br d, 2 H), 1.96 (br d, 2 H), 1.80 - 1.88 (m, 2 H), 1.69 - 1.76 (m, 2 H), 1.21 - 1.47 (m, 4 H).

Step C. Synthesis of 4-(4-((3-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(l- methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)ureido)methyl)phenoxy)butyl 4- methylbenzenesulfonate. To a solution of l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-3-(4-(4-hydroxybutoxy)benzyl)-l-(4-(l-methyl-6-oxo-l,6- dihydropyridin-3-yl)phenyl)urea (210 mg, 338 umol) in DCM (5 mL) was added TsCl (129.00 mg, 677 umol), DMAP (4 mg, 34 umol) and TEA (103 mg, 1 mmol). The mixture was stirred at 25 °C for 2 hrs. The mixture was quenched with saturated NaHCCL (10 mL) and extracted with DCM (50 mL *3). The combined organic layer was washed with citric acid (15 mL), dried over Na₂SO₄, filtered and concentrated in vacuum to give a crude product. The crude product was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=l/0 to 10/1) to give the desired compound 4-(4-((3-((lr,4r)-4-((5- cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ureido)methyl)phenoxy)butyl 4-methylbenzenesulfonate (210 mg) . ¹ H NMR(400 MHz, CDCl₃) d 8.26 (s, 1 H), 7.76 (br d, 2 H), 7.59 (br d, 1 H), 7.50 (s, 1 H), 7.38 - 7.47 (m, 3 H), 7.32 (br d, 2 H), 7.18 (br d, 2 H), 7.08 (br d, 2 H), 6.60 - 6.83 (m, 3 H), 6.26 (d, 1 H), 4.91 (br d, 1 H), 4.59 (br t, 1 H), 4.19 - 4.31 (m, 3 H), 4.04 - 4.12 (m, 2 H), 3.83 - 3.90 (m, 2 H), 3.62 (s, 3 H), 3.52 (br s, 1 H), 2.97 (br s, 1 H), 2.43 (s, 3 H), 2.09 (br d, 2 H), 1.97 (br d, 2 H), 1.73 - 1.83 (m, 4 H), 1.20 - 1.47 (m, 4 H). LCMS [M+H]⁺: 775.3.

Step D. Synthesis of l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(4-((2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)butoxy)benzyl)-l-(4-(l-methyl-6- oxo-1, 6-dihydropyridin-3-yl)phenyl)urea. To a solution of 4-(4-((3-((lr,4r)-4-((5- cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ureido)methyl)phenoxy)butyl 4-methylbenzenesulfonate (100 mg, 129 umol) in DMF (4 mL) was added CS2CO3 (84 mg, 258 umol) and 2-(2,6-dioxo-3-piperidyl)- 4-hydroxy-isoindoline-l,3-dione (35 mg, 129 umol). The mixture was stirred at 80 °C for 2 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The mixture was diluted with brine (15 mL) and extracted with DCM (60 mL *3). The organic layer was washed with brine (20 ml), dried over Na₂SO₄, filtered and evaporated to give a crude product. The crude product was purified by prep-HPLC(column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water(10mM NH₄HCO₃-ACN] ; B%: 32%-62%, 8min) to give the desired compound l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(4-((2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)butoxy)benzyl)-l-(4-(l-methyl-6- oxo-l,6-dihydropyridin-3-yl)phenyl)urea (24 mg). ¹H NMR (400 MHz, DMSO) d 8.21 (d, 1 H), 8.08 (d, 1 H), 7.83 (dd, 1 H), 7.46 - 7.66 (m, 4 H), 7.25 (d, 1 H), 7.15 - 7.20 (m, 3 H), 7.02 (d, 2 H), 6.76 (d, 2 H), 6.37 - 6.54 (m, 2 H), 5.64 (br t, 1 H), 5.07 (dd, 1 H), 4.22 (br t, 1 H), 4.02 (d, 2 H), 3.85 (br t, 2 H), 3.61 - 3.65 (m, 2H), 3.47 (s, 3 H), 2.79 - 2.96 (m, 1 H),

2.62 - 2.74 (m, 1 H), 2.48 - 2.52 (m, 1 H), 1.97 (br s, 1 H), 1.70 - 1.89 (m, 4 H), 1.46 - 1.62 (m, 4 H), 1.19 - 1.36 (m, 2 H), 0.99 - 1.14 (m, 2 H). LCMS [M+H]⁺: 880.2

The procedure set forth above in Example 12 was used to produce following compounds using appropriate starting materials. Standard protection and deprotection can be used when necessary

Example 13. Synthesis of N-(2-((4-(4-(3-benzyl-l-((ls,4s)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)ureido)phenyl)pyridin-2-yl)oxy)ethyl)-2-((2-(2,6-dioxopiperidin-3- yl)-l,3-dioxoisoindolin-4-yl)oxy)acetamide

Step A. Synthesis of 3-(4-(3-((tert-butyldimethylsilyl)oxy)propoxy)benzyl)-l-((lr,4r)-4- ((5-cyanopyridin-2-yl)amino)cyclohexyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)urea To a solution of l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4- hydroxybenzyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea (0.3 g, 5471 umol) and 3 -bromopropoxy-tert-butyl-dimethyl- silane (166 mg, 656 umol) in DMF (2 mL) was added CS2CO3 (356 mg, 1.09 mmol). After the addition was complete, the reaction mixture was stirred at 80°C for 16 hrs. The reaction mixtuer was poured into saturated NH4CI (30 mL). The result mixture was extracted with EtOAc (4 * 15 mL). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (Dichloromethane : Methanol = 50:1 to 20:1) to give the desired product 3-(4-(3-((tert- butyldimethylsilyl)oxy)propoxy)benzyl)-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea (370 mg).

NMR (400 MHz, CDCl₃) d 8.25 (d, 1 H), 7.58 (d, 1 H), 7.36 - 7.51 (m, 4 H), 7.17 (br d, 2 H), 7.06 (br d, 2 H), 6.78 (br d, 2 H), 6.66 (d, 1 H), 6.25 (d, 1 H), 4.89 (br d, 1 H), 4.53 - 4.62 (m, 1 H), 4.26 (br d, 2 H), 4.15 - 4.23 (m, 1 H), 3.98 (t, 2 H), 3.74 (t, 2 H), 3.61 (s, 3 H), 3.43 - 3.55 (m, 1 H), 2.08 (br d, 2 H), 1.88 - 2.01 (m, 4 H), 1.21 - 1.43 (m, 4 H), 0.84 (s, 9 H), 0.00 (s, 6 H).

Step B. Synthesis of l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(3- hydroxypropoxy)benzyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea. To a solution of 3-(4-(3-((tert-butyldimethylsilyl)oxy)propoxy)benzyl)-l-((lr,4r)-4-((5- cyanopyridin-2-yl)amino)cyclohexyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)urea (0.2 g, 277 umol) in THF (5 mL) was added TBAF (1 M in THF, 832 uL). After the addition was complete, the reaction mixture was stirred at 25 °C for 16hrs. The reaction mixture was concentrated to dryness. The residue was purified by column chromatography on silica gel (Dichloromethane: Methanol=50: 1 to 20:1) to give the desired product l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(3- hydroxypropoxy)benzyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea (150 mg, crude).

Step C. Synthesis of l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(3-((2- (2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)oxy)propoxy)benzyl)-l-(4-(l-methyl-6- oxo-1, 6-dihydropyridin-3-yl)phenyl)urea To a solution of l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-3-(4-(3-hydroxypropoxy)benzyl)-l-(4-(l-methyl-6-oxo-l,6- dihydropyridin-3-yl)phenyl)urea (0.1 g, 165 umol), 2-(2,6-dioxo-3-piperidyl)-4-hydroxy- isoindoline-l,3-dione (45 mg, 164.82 umol) and DBAD (76 mg, 330 umol) in THF (3 mL) was added PPh ₃ (86 mg, 330 umol). After the addition was complete, the reaction mixture was stirred at 40°C for 16 hrs. DCM (50 mL) was added into the reaction mixture and result mixture was washed with water (20 mL), brine (20 mL), dried over Na₂SO₄, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (Petroleum ether: Ethyl acetate=10:l to 1:1) to give the desired product l-((lr,4r)-4-((5- cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-4-yl)oxy)propoxy)benzyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)urea (60 mg). NMR (400 MHz, METHANOL-d₄) d 8.23 (d, 1 H), 8.06 (d, 1 H), 7.94 (dd, 1 H), 7.77 (dd, 1 H), 7.67 (d, 2 H), 7.53 (dd, 1 H), 7.45 (dd, 2 H), 7.29 (d, 2 H), 7.11 (d, 2 H), 6.86 (d, 2 H), 6.68 (d, 1 H), 6.47 (d, 1 H), 5.55 (t, 1 H), 5.10 (dd, 1 H), 4.39 - 4.48 (m, 3 H), 4.18 - 4.26 (m, 4 H), 3.68 (s, 3 H), 3.57 (br d, 1 H), 2.66 - 2.92 (m, 3 H), 2.30 (quin, 2 H), 2.02 - 2.16 (m, 3 H), 1.92 - 2.00 (m, 2 H), 1.28 - 1.46 (m, 4 H). LCMS: m/z 432.2 [M+2H]²⁺/2.

Example 14. Synthesis of l-(4-(lH-pyrazol-4-yl)phenyl)-3-benzyl-l-((lr,4r)-4-((5- cyanopyridin-2-yl)amino)cyclohexyl)urea

Step A. Synthesis of l-(4-(lH-pyrazol-4-yl)phenyl)-3-benzyl-l-((lr,4r)-4-((5- cyanopyridin-2-yl)amino)cyclohexyl)urea. A mixture of tert-butyl 4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyrazole-l-carboxylate (3.73 g, 12.69 mmol), 3 -benzyl- 1 -(4- bromophenyl)-l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)urea (3.2 g, 6.34 mmol), Pd(PPh₃)₂Cl₂ (445 mg, 634 umol) and Na₂CO₃ (2.02 g, 19.03 mmol) in dioxane (60 mL) and H2O (30 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 2 hrs under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The mixture was diluted with saturated brine (35 mL) and extracted with ethyl acetate (100 mL *3). The organic layer was washed with brine (20 ml), dried over Na₂SO₄, filtered and evaporated to give a crude product. The crude product was purified by prep-HPLC (column: Boston Prime C18 150*30mm 5um; mobile phase: [water(0.04% NH3H2O + lOmM NH₄HCO₃)-ACN]; B%: 35%-65%,8min) to give the desired compound l-(4-(lH-pyrazol-4-yl)phenyl)-3-benzyl-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)urea (1.39 g). NMR (400 MHz, DMSO-d6) d 12.95 (br s, 1 H), 8.25 (d, 1 H), 7.97 - 8.17 (m, 1 H), 7.65 (d, 2 H), 7.57 (dd, 1.8 Hz, 1 H), 7.45 (br d, 1 H), 7.20 - 7.29 (m, 2 H), 7.07 - 7.18 (m, 5 H), 6.43 (d, 1 H), 5.80 (br t, 1 H), 4.26 (br t, 1 H), 4.12 (br d,

2 H), 3.40 - 3.53 (m, 1 H), 1.88 (br d, 2 H), 1.78 (br d, 2 H), 1.20 - 1.35 (m, 2 H), 1.00 - 1.19 (m, 2 H). LCMS [M+H]⁺: 492.2.

Example 15. Synthesis of 3-((lH-pyrazol-4-yl)methyl)-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea

Step A. Synthesis of tert-butyl ((lr,4r)-4-((4-bromophenyl)amino)cyclohexyl)carbamate.

To a solution of tert-butyl N-(4-aminocyclohexyl)carbamate (5 g, 23.33 mmol) and (4- bromophenyl)boronic acid (4.69 g, 23.33 mmol) in DCM (100 mL) was added TEA (4.72 g, 46.66 mmol), 4A MOLECULAR SIEVE (1 g) and Cu(OAc)₂ (1.27 g, 7.00 mmol). The mixture was stirred at 25 °C for 12 hrs under O2 atmosphere. The mixture was added CU(OAC)2 (0.4g) and (4-bromophenyl)boronic acid (1.3 g) again, and the mixture was stirred at 25°C for another 12 hrs under O2 atmosphere. The mixture was concentrated in vacuum to give a crude product. The crude was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=l/0 to 3:1) to give the desired product tert-butyl ((lr,4r)-4-((4- bromophenyl)amino)cyclohexyl)carbamate (6.3 g). ¹ H NMR(400 MHz, CDCI3) d 7.17 - 7.22 (m, 2 H), 6.32 - 6.50 (m, 2 H), 4.40 (br s, 1 H), 3.47 (br s, 2 H), 3.14 (br s, 1 H), 1.96 - 2.16 (m, 4 H), 1.43 (s, 9 H), 1.11 - 1.29 (m, 4 H) LCMS [M+H]⁺: 371.1 Step B. Synthesis of tert-butyl ((lr,4r)-4-((4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)amino)cyclohexyl)carbamate. A mixture of tert-butyl ((lr,4r)-4-((4- bromophenyl)amino)cyclohexyl)carbamate (5 g, 13.54 mmol), l-methyl-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-one (3.34 g, 14.22 mmol), Pd(PPh3)4 (1.56 g, 1.35 mmol), K2CO3 (3.74 g, 27.08 mmol) and H2O (60 ruL) in dioxane (120 ruL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 4 hrs under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent. The mixture was diluted with saturated brine (50 ruL) and extracted with ethyl acetate (200 ruL *3). The organic layer was washed with brine (30 ml), dried over Na₂SO₄, filtered and evaporated to give a crude product. The crude product was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=l/0 to 0:1) to give the desired compound tert-butyl ((lr,4r)-4-((4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)amino)cyclohexyl)carbamate (3 g). LCMS [M+H]⁺: 398.3.

Step C. Synthesis of 4-cyano-N,N-dimethyl-lH-pyrazole-l-sulfonamide. To a solution of lH-pyrazole-4-carbonitrile (500 mg, 5.37 mmol) in CH3CN (10 mL) was added TEA (815 mg, 8.06 mmol), then to the mixture was added dropwise N,N-dimethylsulfamoyl chloride (848 mg, 5.91 mmol) at 25°C. The mixture was stirred at 50 °C for 15 hrs. The mixture was quenched with saturated brine (10 mL) and extracted with ethyl acetate (20 mL *3). The combined organic layer was washed with brine (15 mL), dried over Na₂SO₄, filtered and concentrated in vacuum to give a crude product. The crude product was purified by column chromatography (SiCL, Petroleum ether/Ethyl acetate=l/0 to 3:1) to give the desired compound 4-cyano-N,N-dimethyl-lH-pyrazole-l- sulfonamide (830 mg). ¹ H NMR(400 MHz, CDCI3) d 8.35 (s, 1 H), 7.94 (s, 1 H), 2.99 - 3.04 (m, 1 H), 2.90 - 3.10 (m, 6 H).

Step D. Synthesis of 4-(aminomethyl)-N,N-dimethyl-lH-pyrazole-l-sulfonamide. To a solution of 4-cyano-N,N-dimethyl-lH-pyrazole- 1-sulfonamide (8.9 g, 44.45 mmol) and NH3.H2O (18.20 g, 20 mL) in MeOH (200 mL) was added Raney Ni (800 mg, 44.45 mmol) under N2 atmosphere. The suspension was degassed and purged with ¾ for 3 times. The mixture was stirred under ¾ (50 psi.) at 25 °C for 15 hrs. The mixture was filtered and concentrated in vacuum to give a crude product. The crude product was purified by column chromatography (SiO₂, Dichloromethane: Methanol=l/0 to 80:1) to give the desired compound 4-(aminomethyl)-N,N-dimethyl-lH-pyrazole-l-sulfonamide (5.6 g). ¹ H NMR (400 MHz, CDCl₃) d 7.87 (s, 1 H), 7.63 - 7.72 (m, 1 H), 3.70 (s, 2 H), 2.91 (s, 6 H).

Step E. Synthesis of 4-nitrophenyl ((l-(N,N-dimethylsulfamoyl)-lH-pyrazol-4- yl)methyl)carbamate. To a solution of (4-nitrophenyl) carbonochloridate (5.10 g, 25.31 mmol) in DCM (50 mL) was added NMM (6.98 g, 69.03 mmol) and 4-(aminomethyl)-N,N- dimethyl-pyrazole- 1 -sulfonamide (4.7 g, 23.01 mmol). The mixture was stirred at 0 °C for 2 hrs. The mixture was diluted with saturated brine (10 mL) and extracted with DCM (20 mL *3). The combined organic layer was washed with brine (15 mL), dried over Na₂SO₄, filtered and concentrated in vacuum to give a crude product. The crude product was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=l/0 to 1:1) to give the desired compound (4-nitrophenyl) N-[[l-(dimethylsulfamoyl)pyrazol-4-yl]methyl]carbamate (5.3 NMR (400 MHz, CDCl₃) d 8.23 (d, 2 H), 7.95 (s, 1 H), 7.65 - 7.77 (m, 1 H), 7.26 - 7.39 (m, 2 H), 5.59 (br s, 1 H), 4.35 (d, 2 H), 2.84 - 3.00 (m, 6 H).

Step F. Synthesis of tert-butyl ((lr,4r)-4-(3-((l-(N,N-dimethylsulfamoyl)-lH-pyrazol-4- yl)methyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ureido)cyclohexyl)carbamate. To a solution of (4-nitrophenyl) N-[[l- (dimethylsulfamoyl)pyrazol-4-yl] methyl] carbamate (1.6 g, 4.33 mmol) in C¾CN (30 mL) was added DMAP (635 mg, 5.20 mmol) and tert-butyl ((lr,4r)-4-((4-(l-methyl-6-oxo-

1.6-dihydropyridin-3-yl)phenyl)amino)cyclohexyl)carbamate (1.55 g, 3.90 mmol). The mixture was stirred at 80 °C for 12 hrs. The mixture was concentrated in vacuum to give a crude product. The crude product was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=l/0 to 0:1 to DCM/MeOH=15:l) to give the desired compound tert-butyl ((lr,4r)-4-(3-((l-(N,N-dimethylsulfamoyl)-lH-pyrazol-4-yl)methyl)-l-(4-(l-methyl-6-oxo-

1.6-dihydropyridin-3-yl)phenyl)ureido)cyclohexyl)carbamate (2.5 g). LCMS [M+H]⁺: 628.4. Step G. Synthesis of 3-((lH-pyrazol-4-yl)methyl)-l-((lr,4r)-4-aminocyclohexyl)-l-(4-(l- methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea hydrochloride. To a solution of tert- butyl ((lr,4r)-4-(3-((l-(N,N-dimethylsulfamoyl)-lH-pyrazol-4-yl)methyl)-l-(4-(l -methyl-6- oxo-1, 6-dihydropyridin-3-yl)phenyl)ureido)cyclohexyl)carbamate (3.6 g, 5.73 mmol) in MeOH (40 mL) was added HCl/MeOH (4 M, 17.20 mL). The mixture was stirred at 25 °C for 15 hrs .The mixture was concentrated under vacuum to give the desired compound 3-((lH-pyrazol-4-yl)methyl)-l-((lr,4r)-4-aminocyclohexyl)-l-(4-(l-methyl-6- oxo-l,6-dihydropyridin-3-yl)phenyl)urea hydrochloride (2.9 g, crude). LCMS [M+H]⁺:

421.2.

Step H. Synthesis of 3-((lH-pyrazol-4-yl)methyl)-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea. To a solution of 3-((lH-pyrazol-4-yl)methyl)-l-((lr,4r)-4-aminocyclohexyl)-l-(4-(l-methyl-6- oxo-l,6-dihydropyridin-3-yl)phenyl)urea hydrochloride (2.9 g, 5.88 mmol) in DMF (100 mL) was added DIPEA (3.80 g, 29.39 mmol) and 6-fluoropyridine-3-carbonitrile (1.44 g,

11.75 mmol). The mixture was stirred at 80 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The mixture was diluted with saturated brine (15 mL) and extracted with DCM (80 mL *3). The organic layer was washed with brine (20 ml), dried over Na₂SO₄, filtered and evaporated to give a crude product. The crude product was purified by column chromatography (SiO2, DCM/MeOH=l/0 to 15:1 ) to give the desired compound 3-((lH-pyrazol-4-yl)methyl)-l-((lr,4r)-4-((5-cyanopyridin-2- yl)amino)cyclohexyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea. (2.5 g). ¹ H NMR (400 MHz, METHAN OL-<d₄) d 8.23 (d, 1 H), 8.08 (d, 1 H), 7.95 (dd, 1 H), 7.68 (d, 2 H), 7.44 - 7.57 (m, 3 H), 7.26 (d, 2 H), 6.69 (d, 1 H), 6.47 (d, 1 H), 4.45 (br t, 1 H), 4.18 (s, 2 H), 3.69 (s, 3 H), 3.46 - 3.61 (m, 1 H), 1.90 - 2.12 (m, 4 H), 1.18 - 1.35 (m, 4 H).

Example 16. Synthesis of l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4- hydroxybenzyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea

Step A. Synthesis of tert-butyl ((lr,4r)-4-(3-(4-methoxybenzyl)-l-(4-(l-methyl-6-oxo-l,6- dihydropyridin-3-yl)phenyl)ureido)cyclohexyl)carbamate. To a solution of tert-butyl ((lr,4r)-4-((4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)amino)cyclohexyl)carbamate (3 g, 7.55 mmol) in MeCN (50 mL) was added DMAP (1.11 g, 9.06 mmol) and (4- nitrophenyl) N-[(4-methoxyphenyl)methyl] carbamate (4.56 g, 15.09 mmol). The mixture was stirred at 80 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2, DCM: MeOH = 100:1 to 10:1) to give desired product tert-butyl ((lr,4r)-4-(3-(4-methoxybenzyl)-l-(4-(l- methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)ureido)cyclohexyl)carbamate (3.5 g). LCMS [M+H]⁺: 561.4.

Step B. Synthesis of l-((lr,4r)-4-aminocyclohexyl)-3-(4-methoxybenzyl)-l-(4-(l-methyl- 6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea. To a solution of tert-butyl ((lr,4r)-4-(3-(4- methoxybenzyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ureido)cyclohexyl)carbamate (3.5 g, 6.24 mmol) in MeOH (20 mL) was added HCl/MeOH (4 M, 5.46 mL). The mixture was stirred at 25 °C for 0.5 hrs. The reaction mixture was concentrated under reduced pressure to give desired product l-((lr,4r)-4- aminocyclohexyl)-3-(4-methoxybenzyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)urea (3.08 g, crude, HC1). LCMS [M+H]⁺: 461.3.

Step C. Synthesis of l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4- methoxybenzyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea. To a solution of l-((lr,4r)-4-aminocyclohexyl)-3-(4-methoxybenzyl)-l-(4-(l-methyl-6-oxo-l,6- dihydropyridin-3-yl)phenyl)urea (3.07 g, 6.18 mmol, HC1) in DMF (20 mL) was added DIPEA (3.99 g, 30.88 mmol) and 6-fluoropyridine-3-carbonitrile (2.26 g, 18.53 mmol). The mixture was stirred at 80 °C for 2 hrs. The reaction mixture was diluted with H2O (100 mL) and extracted with DCM (300 mL) three times. The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2, DCM: MeOH = 100:1 to 10:1) to give desired product 1- ((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-methoxybenzyl)-l-(4-(l -methyl-6- oxo-l,6-dihydropyridin-3-yl)phenyl)urea (2.35 g). LCMS [M+H]⁺: 563.4.

Step D. Synthesis of l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4- hydroxybenzyl)-l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea. To a solution of l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-methoxybenzyl)-l-(4-(l- methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea (1 g, 1.78 mmol) in DCM (30 mL) was added BBr3 (2.67 g, 10.66 mmol) at -78°C. The mixture was stirred at -78°C for 1 hr and at 20 °C for another 2 hrs. The reaction mixture was quenched by addition saturated NaHCO₃ solution (50 ml) at 0 °C, and the reaction mixture was extracted with DCM 300 mL (lOOmL * 3). The combined organic layers were concentrated under reduced pressure to give desired product l-((lr,4r)-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-3-(4-hydroxybenzyl)- l-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)urea (1.15 g, crude). ¹ H NMR (400 MHz, DMSO -d₆) d 9.13 (s, 1 H), 8.25 (d, 1 H), 8.14 (d, 1 H), 7.82 (dd, 1 H), 7.52 - 7.66 (m, 3 H), 7.44 (br d, 1 H), 7.16 (d, 2 H), 6.94 (d, 2 H), 6.61 (d, 2 H), 6.41 - 6.50 (m, 2 H), 5.59 (br t, 1 H), 4.26 (br t, 1 H), 3.48 (s, 3 H), 3.43 (br d, 1 H), 3.13 (s, 2 H), 1.88 (br d, 2 H), 1.78 (br d, 2 H), 1.21 - 1.36 (m, 2 H), 1.04 - 1.14 (m, 2 H); LCMS [M+H]⁺: 549.2.

Example 17. Biochemical potency testing of compounds against CDK12

Recombinant CDK12/Cyclin K complex was produced by double infection in the baculovims/SF9 system using one virus for each protein; the complex was purified by an affinity tag on CDK12 followed by size-exclusion chromatography to recover heterodimeric complex exclusively. Compounds were assayed in a reaction buffer containing (50 mM HEPES pH 7.2, 0.05% (w/v) bovine serum albumin, 20 mM MgCl₂, 1 mM DTT, 0.01% (v/v) Tween-20, 1 mM sodium vanadate, 3% DMSO, 5 uM ATP, 4 uM CDK9tide substrate). In a typical reaction, 50 nM CDK12/CylinK complex was incubated in 20 ul of reaction buffer containing an element of a compound 10-point dose response curve starting at 10 uM and proceeding with three-fold dilutions. Reactions were allowed to proceed for 2 hours at 28C and then the degree of phosphorylation of the substrate was determined by analysis on a Perkin Elmer EZChip reader. Inhibition curves were fit to a four-parameter regression model and the IC50 was extracted.

Example 18. E3 ligase engagement BRET assay

The compounds were evaluated for VHL or CRBN engagement in HCT116 cells using similar protocols as described below. The VHL and CRBN BRET-based engagement assays were performed with the NanoBRET™ TE In-cell CRBN or VHL kits (PROMEGA Cat# CS1810C140 or CS1810C157 respectively) according to the following steps:

1. HCT116 cells were transduced with NanoLuciferase-CRBN or VHL-NanoLucif erase and were routinely grown in growth medium [RPMI1640 (Corning Cat# 10-041-CV), Tet-Free FBS (Takara Cat# 631101)]. 2. At the day of the assay, medium was removed, and cells were washed and dissociated by trypsinization. Trypsin was neutralized by addition of growth medium and cells were pelleted by centrifugation at 200 x g for 5 minutes.

3. Medium was aspirated, cells were resuspended into a single cell suspension using pre- warmed Opti-MEM (Gibco Cat# 11058) without serum or phenol red and cell density was adjusted to 2xl0⁵ cells/ml in Opti-MEM without serum or phenol red.

4. 85ul of cell suspension was dispensed into each well of a white non-binding 96-well plate (Coming Cat# 3600). Cells were periodically mixed to avoid settling of cell suspension.

5. Complete 20X NanoBRET™ Dilution buffer (components included in the NanoBRET™ TE In-cell CRBN or VHL kits) was prepared as follows: a. Prepared 100X solution of NanoBRET™ tracer in pure DMSO (100X solution corresponds to 50uM for CRBN tracer and lOOuM for VHL tracer). b. Mix one part of 100X tracer to 4 parts NanoBRET™ tracer dilution buffer to generate Complete 20X NanoBRET™ Tracer Dilution Buffer (20X solution corresponds to lOuM for CRBN tracer and 20uM for VHL tracer).

6. Added 5ul of Complete 20X NanoBRET™ Tracer Dilution Buffer per well to cells in suspension.

7. Plates were mixed on orbital shaker for 15 seconds at 700 rpm.

8. Prepared serially diluted compounds as follows: a. Initial compound stock of lOmM was diluted 9 times in a 3 -fold dilution scheme in DMSO to generate 9 concentrations (10, 3.333333, 1.111111, 0.37037, 0.123457, 0.041152, 0.013717, 0.004572 and 0.001524 mM) of compound that correspond to 1000X stock solutions. b. Each dilution was further diluted to 10X concentration in Opti-MEM without serum or phenol red. A tenth condition of 1% DMSO in Opti-MEM without serum or phenol red was prepared to act as control.

9. Added lOul/well of 10X serially diluted compound to the 96-well plates containing cells with IX tracer. Each compound testing required 33wells of a 96-well plate: 27 for 9 compound dilutions in triplicate, 3 for DMSO control and 3 for no-tracer control (background correction). For the background correction wells, Opti-MEM with 1% DMSO was added instead of compound. Plates were mixed on orbital shaker for 15 seconds at 700 rpm.

10. Plates were incubated at 37°C in an incubator with 5% CO2 for 30 min. 11. 3X complete NanoBRET™ NanoGlo® substrate (components included in the NanoBRET™ TE In-cell CRBN or VHL kits) was prepared immediumtely prior to BRET measurements in Opti-MEM without serum or phenol red as follows: a. Diluted NanoBRET™ NanoGlo® substrate 1:166 and Extracellular NanoLuc Inhibitor 1:500 in Opti-MEM without serum or phenol red. b. Mixed gently by inversion 5-10 times.

12. Added 50ul of 3X complete NanoBRET™ NanoGlo® substrate per well of a 96-well plate and incubated 2-3min at room temperature.

13. Measured donor emission (450nm) and acceptor emission (610nm) using the GloMAX® Discover plate reader (PROMEGA Cat# GM3000) with the NanoBRET™ 618 pre-installed protocol.

14. BRET raw ratio values were calculated by dividing the acceptor emission value (610nm) by the donor emission value (450nm) for each well.

15. For background correction, the average raw BRET ratio of the well without tracer were subtracted from the wells with tracer.

16. Raw BRET values for DMSO treated cells were set to 100 and the raw BRET values of the compound treated were expressed as % of the DMSO control (relative BRET values).

17. Relative BRET values were plotted as a function of the loglO of the concentration of compound and data points were fitted to a non-linear curve using the variable regression model in GraphPad Prism (version 8) from which the concentration leading to 50% max effect (IC50) was calculated.

Example 19. Protein degradation assay

The compounds were evaluated for CDK12 degradation in HCT116 cells engineered to carry homozygous insertion of the HiBit tag (PROMEGA, DNA sequence GTG AGC GGCT GGCGGCT GTT C A AG A AG ATT AGC ) in the C-terminus of the CDK12 gene (HCT116 CDK12-HiBit cells). Levels of HiBit that directly correspond to CDK12 levels were detected using the NanoGlo® HiBit Lytic Detection System (PROMEGA Cat# N3050) and cell viability was quantitated using the CellTiter-Glo® Luminescent Cell Viability Assay (PROMEGA Cat# G7573) according to the following steps:

1. HCT116 CDK12-HiBit cells were routinely maintained in growth medium

[RPMI1640 (Coming Cat# 10-041-CV), Tet-Free FBS (Takara Cat# 631101)]. 2. At day 0, medium was removed, and cells were washed and dissociated by trypsinization. Trypsin was neutralized by addition of growth medium and cells were pelleted by centrifugation at 200 x g for 5 minutes.

3. Medium was aspirated, cells were resuspended into a single cell suspension using pre- warmed growth medium and cell density was adjusted to 5xl0³ cells/ml in growth medium.

4. lOOul of cell suspension was dispensed into each well of a white tissue culture treated plate (Corning Cat# 3917). Plates were returned to incubator set at 37°C with 5% CO2 and cells were allowed to attach overnight.

5. At day 1, medium was aspirated from 96- well plates and 90ul/well of fresh growth medium was added.

6. Serially diluted compounds were prepared as follows: a. Initial compound stock of lOmM was diluted 9 times in a 3 -fold dilution scheme in DMSO to generate 9 concentrations (10, 3.333333, 1.111111, 0.37037, 0.123457, 0.041152, 0.013717, 0.004572 and 0.001524 mM) of compound that correspond to 1000X stock solutions. b. Each dilution was further diluted to 10X concentration growth medium. A tenth condition of 1% DMSO in growth medium was prepared to act as control.

7. Added lOul/well of 10X serially diluted compound to the 96- well plates. Each compound testing required 60 wells of a 96-well plate: 30 for 9 compound dilutions + DMSO in triplicate for HiBit measurement and 30 for viability measurement. Plates were mixed on orbital shaker for 15 seconds at 700 rpm.

8. Plates were incubated at 37°C in an incubator with 5% CO2 for 24 hrs.

9. At the time of the assay (day 2), Nano-Glo® HiBit Lytic Detection Reagent and CellTiter-Glo Reagent were prepared as follows: a. Nano-Glo® HiBit Lytic Detection Reagent is prepared by diluting the LgBiT protein 1:100 and the Nano-Glo® HiBiT Lytic Substrate 1:50 in Nano-Glo Lytic Buffer (components included in NanoGlo® HiBit Lytic Detection System). b. CellTiter-Glo® Reagent is prepared by dissolving the CellTiter-Glo® Substrate in CellTiter-Glo® Buffer (components included in CellTiter-Glo® Luminescent Cell Viability Assay). 10. Added lOOul of Nano-Glo® HiBit Lytic Detection Reagent or per well (30 wells each).

11. Plates were mixed on orbital shaker for 1 minute at 700 rpm.

12. Luminescence was measured using the GloMAX® Discover plate reader (PROMEGA Cat# GM3000) using the pre-installed Luminesence protocol

(integration time=0.3 seconds).

13. Normalized CDK12 levels were calculated by dividing the HiBiT signal to the CellTiter-Glo® signal.

18. Relative CDK12 levels were calculated as a % of the DMSO control, were plotted as a function of the log 10 of the concentration of compound and data points were fitted to a non-linear curve using the variable regression model in GraphPad Prism (version 8) from which the concentration leading to 50% max effect (IC50) and maximum effect were calculated. This invention will be better understood from the Examples that follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the claims which follow thereafter, and are not to be considered in any way limited thereto.

Claims

Listing of Claims:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein

Ring A is 5- or 6-membered heteroaryl or 5- or 6-membered heterocyclyl, each of which is substituted with 0-4 occurrences of R^a;

R¹ is -NRⁿ²R⁴ and R² is -L'-R³; or R¹ is L°-Ring B-L'-R³ and R² is hydrogen or C₁-C₆ alkyl;

L° is a bond or C1-C3 hydrocarbon chain, wherein one or more carbon units of the hydrocarbon chain is optionally replaced with -O-, -S-, -NRⁿ³-, -NRⁿ³C(=O)-, - C(=O)NRⁿ³-, -NRⁿ³C(=O)O-, -OC(=O)NRⁿ³-, - NR^nlC(=O)NRⁿ³-, -C(=O)-, -OC(=O)-, or -C(=O)O-; each instance of L¹ is independently ^a-(CH₂)_x - [(CH₂)_m O]_n -(CH₂)_y- L² ; a indicates the point of attachment to Ring A or Ring B;

L² is a bond, -O-, -S-, -NRⁿ³-, -C(=O)-, -OC(=O)-, -C(=O)O-, - NRⁿ³C(=O)-, -C(=O)NRⁿ³-, -NRⁿ³C(=O)O-, -OC(=O)NRⁿ³-, - NRⁿ³C(=O)NRⁿ³-, - NRⁿ³C(=O)CH₂O-, or -OCH₂C(=O)NRⁿ³-; and

Ring B is 5- or 6-membered heteroaryl or phenyl, each of which is substituted with 0- 4 occurrences of R^b; each instance of R³ is independently selected from one of the following formulae:

R^o1 is hydrogen, C₁-C₆ alkyl, or an oxygen protecting group.

2. The compound of Claim 1, wherein the compound is of Formula II,

or a pharmaceutically acceptable salt thereof.

3. The compound of any one of Claim 1 or 2, wherein the compound is of Formula Il-a:

or a pharmaceutically acceptable salt thereof.

4. The compound of any one of Claim 1 or 2, wherein the compound is of Formula Il-b:

or a pharmaceutically acceptable salt thereof.

5. The compound of any one of Claim 1 or 2, wherein the compound is of Formula II-c:

or a pharmaceutically acceptable salt thereof.

6. The compound of any one of Claim 1 or 2, wherein the compound is of Formula Il-d:

(Il-d), or a pharmaceutically acceptable salt thereof.

7. The compound of Claim 1, wherein the compound is of Formula III:

or a pharmaceutically acceptable salt thereof.

8. The compound of Claim 7, wherein the compound is of Formula Ill-a:

or a pharmaceutically acceptable salt thereof.

9. The compound of Claim 7, wherein the compound is of Formula Ill-b:

or a pharmaceutically acceptable salt thereof.

10. The compound of any one of Claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R³ is of Formula (i).

11. The compound of any one of Claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R³ is of Formula (ii).

12. The compound of any one of Claims 1 to 7, 10, and 11, or a pharmaceutically acceptable salt thereof, wherein Ring A is pyrazolyl, pyridinyl, or pyridinyl-2-one, each of which is substituted with 0-4 occurrences of R^a.

13. The compound of any one of Claims 1 to 7 and 10 to 12, or a pharmaceutically acceptable salt thereof, wherein Ring A is pyrazolyl, pyridinyl, or pyridinyl-2-one, each of which are unsubstituted.

14. The compound of any one of Claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein ^a-(CH₂)_x-[(CH₂)_mO]_n-(CH₂)_y- is ^a-(CH₂)_z1-(CH₂OCH₂)_z2- or ^a- (OCH₂CH₂)_Z1-(CH₂)_z2; wherein each instance of zl and z2 is independently 0 or an integer from 1 to 10 included.

15. The compound of any one of Claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein ^a-(CH₂)_x-[(CH₂)_mO]_n-(CH₂)_y- is selected from one of the following formulae: ^a-(CH₂)₂OCH₂-, ^a-(CH₂)₃OCH₂-, ^a-(CH₂)₄OCH₂-, ^a-(CH₂O)₂CH₂-, ^a-(CH₂O)₃CH₂-, ^a-(CH₂O)₄CH₂-, ^a-(CH₂O)₅CH₂-, ^a-(CH₂O)₆CH₂-, ^a-(CH₂O)₃(CH₂)₂-, ^a-(CH₂CH₂O)₃CH₂-, ^a- (CH₂CH₂O)₄CH₂-, ^a-(CH₂CH₂O)₅CH₂-, ^a-(CH₂CH₂O)₆CH₂-, ^a-[(CH₂)₄O]₂CH₂-, CH₂(CH₂CH₂O)₂CH₂-, ^a-CH₂(CH₂CH₂O)₂(CH₂)₂-, ^a-CH₂(CH₂CH₂O)₄CH₂-, ^a- CH₂[(CH₂)₄O]₃CH₂-, ^a-(CH₂)₂[(CH₂)₂O]₅CH₂-, ^a-(CH₂)₂(CH₂CH₂O)₅CH₂-, ^a- (CH₂)₂(CH₂CH₂O)₂CH₂-, ^a-(CH₂O)₂(CH₂)₄OCH₂- , ^a-(CH₂)₄O-(CH₂)₃O(CH₂)₄OCH₂-, ^a- (CH₂)₂(CH₂CH₂O)₅[(CH₂)₄O]CH₂-, ^a-(CH₂CH₂O)₂[(CH₂)₄O]CH₂-, ^a-[(CH₂)₄O] [(CH₂)₃O] [(CH₂)₄O]CH₂-, -O(CH₂)₂-, -O(CH₂)₃-, -O(CH₂)₄-, -O(CH₂)₂O-, -O(CH₂)₃O-, -O(CH₂)₄O-, ^a- OCH₂ CH₂OCH₂-, ^a-O(CH₂CH₂O)₂CH₂-, ^a-O(CH₂CH₂O)₃CH₂-, ^a-O(CH₂CH₂O)₄CH₂-, ^a- O(CH₂CH₂O)₅CH₂-, ^a-O(CH₂CH₂O)₆CH_2, ^a-OCH₂CH₂O(CH₂)₂-, ^a-O(CH₂CH₂O)₂(CH₂)₂-, ^a- O(CH₂CH₂O)₃(CH₂)₂-, ^a-O(CH₂CH₂O)₄(CH₂)₂- , ^a-O(CH₂CH₂O)₅(CH₂)₂-, ^a- O(CH₂CH₂O)₆(CH₂)_2-, ^a-OCH₂CH₂O(CH₂)₃-, ^a-O(CH₂CH₂O)₂(CH₂)₃-, ^a- O(CH₂CH₂O)₃(CH₂)₃-, ^a-O(CH₂CH₂O)₄(CH₂)₃- , ^a-O(CH₂CH₂O)₅(CH₂)₃-, ^a- O(CH₂CH₂O)₆(CH₂)_3-, ^a-0 CH₂CH₂O(CH₂)₄-, ^a-O(CH₂CH₂O)₂(CH₂)₄-, ^a- O(CH₂CH₂O)₃(CH₂)₄-, ^a-O(CH₂CH₂O)₄(CH₂)₄- , ^a-O(CH₂CH₂O)₅(CH₂)₄-, ^a- O(CH₂CH₂O)₆(CH₂)_4-, ^a-OCH₂CH₂O(CH₂)₄O(CH₂)₄- , ^a-OCH₂CH₂O(CH₂)₄O(CH₂)₅-, ^a- OCH₂CH₂O[(CH₂)₄O]₂(CH₂)₄-, ^a-OCH₂CH₂O[(CH₂)₄O]₂(CH₂)₅-, ^a- OCH₂CH₂O[(CH₂)₄O][(CH₂)₂O](CH₂)₂-, ^a-OCH₂CH₂O[(CH₂)₄O][(CH₂)₂O](CH₂)₄-, OCH₂CH₂O[(CH₂)₄O][(CH₂)₃O](CH₂)₂-, ^a-OCH₂CH₂O[(CH₂)₄O][(CH₂)₃O](CH₂)₄-, OCH₂CH₂O[(CH₂)₄O][(CH₂)₄O](CH₂)₂-, ^a-OCH₂CH₂O[(CH₂)₄O][(CH₂)₄O](CH₂)₄-, OCH₂CH₂O[(CH₂)₄O][(CH₂)₂O](CH₂)₄CH₂-, or OCH₂CH₂O[(CH₂)₄O] [(CH₂)₂O] (CH₂)₄(CH₂)₂- .

16. The compound of any one of Claims 1-6 and 10 to 15, or a pharmaceutically acceptable salt thereof, wherein R⁴ is CH₃, C₂H₅, or benzyl.

17. The compound of any one of Claims 1 and 7 to 16, or a pharmaceutically acceptable salt thereof, wherein Ring B is pyrazolyl or phenyl, each of which is substituted with 0-1 occurrences of R^b.

18. The compound of any one of Claims 1 and 7 to 17, or a pharmaceutically acceptable salt thereof, wherein Ring B is pyrazolyl or phenyl, each of which is unsubstituted.

19. The compound of any one of Claims 1 to 9 and 11 to 18, or a pharmaceutically acceptable salt thereof, wherein R^o1 is hydrogen or CH₃.

20. The compound of any one of Claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R^nl is hydrogen or CH3.

21. The compound of any one of Claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein Rⁿ² is hydrogen or CH3.

22. The compound of any one of Claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein Rⁿ³ is hydrogen or CH3.

23. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any one in Table 1.

24. A pharmaceutical composition comprising a compound of Claims 1 to 22, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

25. A method of treating cancer in a subject comprising administering to the subject a compound of any one of Claims 1 to 22, or a pharmaceutically acceptable salt thereof.

26. The method of Claim 25, wherein the cancer is a glioblastoma, endometrial carcinoma, melanoma, prostate cancer, breast cancer, or ovarian cancer.