SPIROCYCLIC ANDROGEN RECEPTOR PROTEIN DEGRADERS

Abstract

The present disclosure provides compounds represented by Formula (I) and the salts or solvates thereof, wherein R3a, E, L, A1, B1, X1, X2, Z1, and Z2 are as defined in the specification. Compounds having Formula (I) are androgen receptor degraders useful for the treatment of cancer and other diseases.

Description

BACKGROUND OF THE INVENTION

Field of the Invention

The present disclosure provides heterobifunctional small molecules as androgen receptor (AR) protein degraders. AR degraders useful for the treatment of a variety of diseases including cancer.

Background

Despite improvements in medical treatments over the past three decades, prostate cancer is significant cause of cancer-related death, and is second only to lung cancer among men in developed countries. Hamdy et al., N Engl J Med, 2016, 375, 1415-1424; Litwin and Tan, H. J. JAMA, 2017, 317, 2532-2542. In addition to surgery and radiotherapy, androgen deprivation therapies (ADT) are front-line treatments for prostate cancer patients with high-risk localized disease, and second-generation anti-androgens such as abiraterone and enzalutamide have been shown to benefit patients with advanced prostate cancer. Karantanos et al., Oncogene. 2013, 32, 5501-511; Harris et al., Nat Clin Pract Urol, 2009, 6, 76-85. Nevertheless, patients who progress to metastatic castration-resistant prostate cancer (mCRPC), a hormone-refractory form of the disease, face a high mortality rate and no cure is currently available. Narayanan et al., Oncoscience. 2017, 4, 175-177; Crowder et al., Endocrinology. 2018, 159, 980-993.

The androgen receptor (AR) and its downstream signaling play a critical role in the development and progression of both localized and metastatic prostate cancer. Previous strategies that successfully target AR signaling have focused on blocking androgen synthesis by drugs such as abiraterone and inhibition of AR function by AR antagonists such as enzalutamide and apalutamide (ARN-509). Watson et al., Nat Rev Cancer. 2015, 15, 701-711. However, such agents become ineffective in advanced prostate cancer with AR gene amplification, mutation, and alternate splicing. Balbas et al., Elife. 2013, 2, e00499; Lottrup et al., J Clin Endocrinol Metab. 2013, 98, 2223-2229. But in most patients with CRPC, the AR protein continues to be expressed and tumors are still dependent upon AR signaling. Consequently, AR is an attractive therapeutic target for mCRPC. Zhu et al., Nat Commun. 2018, 9, 500; Munuganti et al., Chem Biol. 2014, 21, 1476-485.

The Proteolysis Targeting Chimera (PROTAC) strategy has gained momentum with its promise in the discovery and development of completely new types of small molecule therapeutics by inducing targeted protein degradation. Raina et al., Proc Natl Acad Sci USA. 2016, 113, 7124-7129; Zhou et al., J. Med. Chem. 2018, 61, 462-481.

A PROTAC molecule is a heterobifunctional small molecule containing one ligand, which binds to the target protein of interest, and a second ligand for an E3 ligase system, tethered together by a chemical linker. Bondeson, D. P.; Crews, C. M. Targeted Protein Degradation by Small Molecules. Annu Rev Pharmacol Toxicol. 2017, 57, 107-123. Because AR protein plays a key role in CRPC, AR degraders designed based upon the PROTAC concept could be effective for the treatment of CRPC when the disease becomes resistant to AR antagonists or to androgen synthesis inhibitors. Salami et al., Commun Biol. 2018, 1, 100; Pal et al., Cancer. 2018, 124, 1216-1224; Wang et al., Clin Cancer Res. 2018, 24, 708-723; Gustafson et al., Angew. Chem. Int. Ed. 2015, 54, 9659-9662. Naito et al. have recently reported AR degraders designed based upon the PROTAC concept, which were named Specific and Nongenetic IAP-dependent Protein Erasers (SNIPERs). Shibata et al., J. Med. Chem. 2018, 61, 543-575.

While SNIPER AR degraders are effective in inducing partial degradation of the AR protein in cells, they also induce the auto-ubiquitylation and proteasomal degradation of the cIAP1 protein, the E3 ligase needed for induced degradation of AR protein, thus limiting their AR degradation efficiency and therapeutic efficacy.

(4R)-1-((S)-2-(2-(4-((4′-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-[1,1′-biphenyl]-4-yl)oxy)butoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide ((ARCC-4) was recently reported as another PROTAC degrader, which was designed using enzalutamide as the AR antagonist and a von Hippel-Lindau (VHL) ligand. Salami et al., Commun Biol. 2018, 1, 100; US 20170327469. ARCC-4 was shown to be more potent and effective than enzalutamide at inducing apoptosis and inhibiting proliferation of AR-amplified prostate cancer cells. ARD-69 was also recently reported as a PROTAC AR degrader. Han et al., J. Med. Chem. 62:941-964 (2019).

There is a need in the art for additional AR degraders to treat prostate cancer and other diseases.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the present disclosure provides heterobifunctional small molecules represented by any one or more of Formulae I, III-VIII, XV, or XVI, below, and the pharmaceutically acceptable salts and solvates, e.g., hydrates, thereof. These compounds are collectively referred to herein as “Compounds of the Disclosure.” Compounds of the Disclosure are androgen receptor (AR) degraders and are thus useful in treating diseases or conditions wherein degradation of the androgen receptor protein provides a therapeutic benefit to a subject.

In another aspect, the present disclosure provides compounds represented by any one or more of Formulae II or IX-XIV, below, and salts and solvates thereof. These compounds are collectively referred to herein as “Intermediates of the Disclosure.” Intermediates of the Disclosure can be used to make the heterobifunctional Compounds of the Disclosure.

In another aspect, the present disclosure provides methods of treating a condition or disease by administering a therapeutically effective amount of a Compound of the Disclosure to a subject, e.g., a human cancer patient, in need thereof. The disease or condition treatable by degradation of the androgen receptor is, for example, a cancer, e.g., prostate cancer, e.g., metastatic castration-resistant prostate cancer.

In another aspect, the present disclosure provides a method of degrading, e.g., reducing the level of, of androgen receptor protein in a subject in need thereof, comprising administering to the individual an effective amount of at least one Compound of the Disclosure.

In another aspect, the present disclosure provides a pharmaceutical composition comprising a Compound of the Disclosure and an excipient and/or pharmaceutically acceptable carrier.

In another aspect, the present disclosure provides a composition comprising a Compound of the Disclosure and an excipient and/or pharmaceutically acceptable carrier for use treating diseases or conditions wherein degradation of the androgen receptor provides a benefit, e.g., cancer.

In another aspect, the present disclosure provides a composition comprising: (a) a Compound of the Disclosure; (b) a second therapeutically active agent; and (c) optionally an excipient and/or pharmaceutically acceptable carrier.

In another aspect, the present disclosure provides a Compound of the Disclosure for use in treatment of a disease or condition of interest, e.g., cancer.

In another aspect, the present disclosure provides a use of a Compound of the Disclosure for the manufacture of a medicament for treating a disease or condition of interest, e.g., cancer.

In another aspect, the present disclosure provides a kit comprising a Compound of the Disclosure, and, optionally, a packaged composition comprising a second therapeutic agent useful in the treatment of a disease or condition of interest, and a package insert containing directions for use in the treatment of a disease or condition, e.g., cancer.

In another aspect, the present disclosure provides methods of preparing Compounds of the Disclosure.

Additional embodiments and advantages of the disclosure will be set forth, in part, in the description that follows, and will flow from the description, or can be learned by practice of the disclosure. The embodiments and advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only, and are not restrictive of the invention as claimed.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is an image of the Western blotting analysis of AR protein levels in prostate cancer VcaP cells treated with Cpd. No. 307 for 24 h at the concentrations indicated. GAPDH was used as the loading control.

FIG. 2 is an image of the Western blotting analysis of AR protein levels in prostate cancer VcaP cells treated with Cpd. No. 293 for 24 h at the concentrations indicated. GAPDH was used as the loading control.

FIG. 3 is an image of the Western blotting analysis of AR protein levels in prostate cancer 22RV1 cells treated with Cpd. No. 307 for 24 h at the concentrations indicated. GAPDH was used as the loading control.

FIG. 4 is an image of the Western blotting analysis of AR protein levels in prostate cancer 22RV1 cells treated with Cpd. No. 293 for 24 h at the concentrations indicated. GAPDH was used as the loading control.

FIG. 5 is an image of the Western blotting analysis of AR protein levels in prostate cancer LNCaP cells treated with Cpd. No. 307 for 24 h at the concentrations indicated. GAPDH was used as the loading control.

FIG. 6 is an image of the Western blotting analysis of AR protein levels in prostate cancer LNCaP cells treated with Cpd. No. 293 for 24 h at the concentrations indicated. GAPDH was used as the loading control.

FIG. 7 is an image of the Western blotting analysis of AR protein levels in prostate cancer VCaP cells treated with 3 nM and 10 nM of Cpd. No. 307 and Cpd. No. 293 at the time points indicated. GAPDH was used as the loading control.

FIG. 8 is an image of the Western blotting analysis of AR protein levels in prostate cancer 22RV1 cells treated with 3 nM and 10 nM of Cpd. No. 307 and Cpd. No. 293 at the time points indicated. GAPDH was used as the loading control.

FIG. 9 is an image of the Western blotting analysis of AR protein levels in prostate cancer LNCaP cells treated with 3 nM and 10 nM of Cpd. No. 307 and Cpd. No. 293 at the time points indicated. GAPDH was used as the loading control.

FIG. 10 is five images of the Western blotting analysis of AR protein levels in the prostate cancer cell line indicated treated with the Compound of the Disclosure indicated for 24 h at the concentrations indicated. GAPDH was used as the loading control.

FIG. 11 is two images of the Western blotting analysis of AR protein levels in the VCaP prostate cancer cell line treated with the Compound of the Disclosure indicated for 24 h at 10 nM and 100 nM. GAPDH was used as the loading control.

FIG. 12 is two images of the Western blotting analysis of AR protein levels in the VCaP prostate cancer cell line treated with the Compound of the Disclosure indicated for 24 h at 10 nM and 100 nM. GAPDH was used as the loading control.

FIG. 13 is an image of the Western blotting analysis of AR protein levels in prostate cancer VcaP cells treated with Cpd. No. 122 for 24 h at the concentrations indicated. GAPDH was used as the loading control.

FIG. 14 is four images of the Western blotting analysis of AR protein levels in prostate cancer VcaP cells treated with the Compound of the Disclosure indicated for 24 h at the concentrations indicated. GAPDH was used as the loading control.

FIG. 15 is a line graph showing the antitumor activity of Cpd. No. 307 in the AR-positive VCaP xenograft model in SCID mice. Cpd. No. 307 was administered via oral gavage daily starting at day 18 for three weeks.

FIG. 16 is a line graph showing the antitumor activity of Cpd. No. 293 in the AR-positive VCaP xenograft model in SCID mice. Cpd. No. 293 was administered via oral gavage daily starting at day 18 for three weeks.

FIG. 17 is four images of the Western blotting analysis of AR protein levels in VCaP or MDA-MB-453 cells treated with Cpd. No. 200 under the conditions indicated in connection with each analysis. GAPDH was used as the loading control.

FIG. 18 is four images of the Western blotting analysis of AR protein levels in VCaP or MDA-MB-453 cells treated with Cpd. No. 201 under the conditions indicated in connection with each analysis. GAPDH was used as the loading control.

FIG. 19 is six images of the Western blotting analysis of AR protein levels in VCaP, LNCaP, or 22RV1 cells treated with Cpd. No. 202 under the conditions indicated in connection with each analysis. GAPDH was used as the loading control

FIG. 20 is four images of the Western blotting analysis of AR protein levels in VCaP or LNCaP cells treated with Cpd. No. 203 under the conditions indicated in connection with each analysis. GAPDH was used as the loading control.

FIG. 21 is four images of the Western blotting analysis of AR protein levels in VCaP or LNCaP cells treated with Cpd. No. 206 under the conditions indicated in connection with each analysis. GAPDH was used as the loading control.

FIG. 22 is four images of the Western blotting analysis of AR protein levels in VCaP or LNCaP cells treated with Cpd. No. 207 under the conditions indicated in connection with each analysis. GAPDH was used as the loading control.

FIG. 23 is four images of the Western blotting analysis of AR protein levels in VCaP or LNCaP cells treated with Cpd. No. 208 under the conditions indicated in connection with each analysis. GAPDH was used as the loading control.

FIG. 24 is four images of the Western blotting analysis of AR protein levels in VCaP or LNCaP cells treated with Cpd. No. 209 under the conditions indicated in connection with each analysis. GAPDH was used as the loading control.

FIG. 25 is four images of the Western blotting analysis of AR protein levels in LNCaP or MDA-MB-453 cells treated with Cpd. No. 152 under the conditions indicated in connection with each analysis. GAPDH was used as the loading control.

FIG. 26 is three images of the Western blotting analysis of AR protein levels in VCaP, LNCaP, or MDA-MB-453 cells treated with Cpd. No. 159 under the conditions indicated in connection with each analysis. GAPDH was used as the loading control.

FIG. 27 is three images of the Western blotting analysis of AR protein levels in VCaP, LNCaP, or MDA-MB-453 cells treated with Cpd. No. 160 under the conditions indicated in connection with each analysis. GAPDH was used as the loading control.

FIG. 28 is a line graph showing the antitumor activity of enzalutamide, Cpd. No. 305, and Cpd. No. 307 in the AR-positive VCaP xenograft model in SCID mice. The compounds were administered via oral gavage daily starting at day 21.

FIG. 29 is a line graph showing the antitumor activity of enzalutamide, Cpd. No. 444, and Cpd. No. 445 in the AR-positive VCaP xenograft model in SCID mice. The compounds were administered via oral gavage daily starting at day 21.

FIG. 30 is a line graph showing the antitumor activity of enzalutamide, Cpd. No. 443, and Cpd. No. 490 in the AR-positive VCaP xenograft model in SCID mice. The compounds were administered via oral gavage daily starting at day 21.

FIG. 31 is a line graph showing the antitumor activity of enzalutamide, Cpd. No. 497, and Cpd. No. 499 in the AR-positive VCaP xenograft model in SCID mice. The compounds were administered via oral gavage daily starting at day 21.

FIG. 32 is a line graph showing the antitumor activity of enzalutamide, Cpd. No. 498, and Cpd. No. 500 in the AR-positive VCaP xenograft model in SCID mice. The compounds were administered via oral gavage daily starting at day 21.

FIG. 33 is a line graph showing the antitumor activity of enzalutamide, Cpd. No. 302, and Cpd. No. 305 in the AR-positive VCaP xenograft model in SCID mice. The compounds were administered via oral gavage daily starting at day 16.

FIG. 34 is a line graph showing the antitumor activity of enzalutamide, Cpd. No. 344, and Cpd. No. 540 in the AR-positive VCaP xenograft model in SCID mice. The compounds were administered via oral gavage daily starting at day 16.

FIG. 35 is a line graph showing the antitumor activity of enzalutamide and Cpd. No. 503 in the AR-positive VCaP xenograft model in SCID mice. The compounds were administered via oral gavage daily starting at day 16.

DETAILED DESCRIPTION OF THE INVENTION

I. Compounds of the Disclosure

Compounds of the Disclosure are heterobifunctional AR degraders. In one embodiment, Compounds of the Disclosure are compounds of Formula I:

wherein:

R^3a is selected from the group consisting of halo, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;

Z¹ is selected from the group consisting of ═C(H)— and ═N—;

Z² is selected from the group consisting of ═C(R^3b)— and ═N—;

R^3b is selected from the group consisting of hydrogen, halo, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;

E is a spiroheterocyclenyl;

X¹ is selected from the group consisting of —C(═O)—, —S(═O)₂—, and —CR^4aR^4b—; or

X¹ is absent;

R^4a and R^4b are independently selected from the group consisting of hydrogen and C₁-C₃ alkyl;

A¹ is selected from the group consisting of cycloalkylenyl, heterocyclenyl, phenylenyl, and heteroarylenyl;

X² is selected from the group consisting of —C(═O)—, —S(═O)₂—, —O—, and —CR^4cR^4d—; or

X² is absent;

R^4c and R^4d are independently selected from the group consisting of hydrogen and C_1-3 alkyl;

L is -J¹-J²-J³-J⁴-J⁵-,

wherein J¹ is attached to X².

J¹ is selected from the group consisting of cycloalkylenyl and heterocyclenyl; or

J¹ is absent;

J² is selected from the group consisting of —(CH₂)_m1—, —CH═CH—, and —C≡C—;

m1 is 0, 1, 2, or 3;

J³ is selected from the group consisting of alkylenyl, heteroalkylenyl, cycloalkylenyl, heterocyclenyl, phenylenyl, and heteroarylenyl; or

J³ is absent;

J⁴ is selected from the group consisting of alkylenyl, cycloalkylenyl, and heterocyclenyl; or

J⁴ is absent;

J⁵ is selected from the group consisting of —(CH₂)_m2—, —O—, —N(R⁶)—, and —C(═O)—;

m2 is 0, 1, 2, or 3;

R⁶ is selected from the group consisting of hydrogen and C₁-C₃ alkyl;

B¹ is selected from the group consisting of:

R^2a, R^2b, R^2c, R^2d, R^2e, R^2f, and R^2g are independently selected from the group consisting of hydrogen, halo, C₁-C₃ alkyl, and C₁-C₃ alkoxy;

R³ is selected from the group consisting of hydrogen, deuterium, fluoro, and C₁-C₃ alkyl;

m is 1, 2, or 3;

n is 1, 2, or 3;

o is 1, 2, or 3;

p is 1, 2, or 3;

Z is selected from the group consisting of —CR^1jR^1k— and —C(═O);

R^1j and R^1k are independently selected from the group consisting of hydrogen and C₁-C₃ alkyl; or R^1j and R^1k taken together with the carbon to which they are attached from a C₃-C₆ cycloalkyl; and

R⁸ is selected from the group consisting of hydrogen and C₁-C₃ alkyl, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of Formula I, and Intermediates of the Disclosure are compounds of Formula II, below, wherein Z is selected from the group consisting of —CH₂— and —C(═O)—, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of Formula I, and Intermediates of the Disclosure are compounds of Formula II, wherein B¹ is selected from the group consisting of B¹-1, B¹-2, B¹-3, B¹-4, B¹-5, B¹-6, and B¹-7, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of Formula I, and Intermediates of the Disclosure are compounds of Formula II, wherein E is selected from the group consisting of:

wherein the bond designated with an “*” is attached to X¹;

o and p are independently 0 or 1;

q and r are independently 0, 1, 2, or 3;

wherein the sum of o, p, q, and r is 2, 3, 4, 5, 6, or 7;

s is 0, 1, 2, 3, or 4;

t, u, v, w, and x are independently 0, 1, 2, or 3;

R^1a and R^1b are independently selected from the group consisting of hydrogen, C₁-C₃ alkyl, C₁-C₄ haloalkyl, optionally substituted C₃-C₆ cycloalkyl, and (C₃-C₆ cycloalkyl)C₁-C₆ alkyl; or

R^1a and R^1b taken together with the carbon atom to which they are attached form an —C(═O)— group; or

R^1a and R^1b taken together with the carbon atom to which they are attached form an optionally substituted C₃-C₆ cycloalkyl; or

R^1a and R^1b taken together with the carbon atom to which they are attached form an optionally substituted 4- to 6-membered heterocyclo;

R^1c and R^1d are independently selected from the group consisting of hydrogen and C₁-C₃ alkyl; or

R^1c and R^1d taken together with the carbon atom to which they are attached form an —C(═O)— group;

each R^1e is independently C₁-C₃ alkyl;

j is 0, 1, 2, 3, or 4;

each R^1f is independently C₁-C₃ alkyl;

k is 0, 1, 2, 3, or 4;

each R^1g is independently C₁-C₃ alkyl; and

h is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of Formula I, and Intermediates of the Disclosure are compounds of Formula II, wherein E is E-1, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of Formula I, and Intermediates of the Disclosure are compounds of Formula II, wherein E 1 is selected from the group consisting of:

or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of Formula I, and Intermediates of the Disclosure are compounds of Formula II, wherein E-1 is E-1-1, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of Formula I, and Intermediates of the Disclosure are compounds of Formula II, wherein E-1 is E-1-1; and R^1a and R^1b are hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of Formula I, and Intermediates of the Disclosure are compounds of Formula II, wherein E-1 is E-1-1; and R^1a and R^1b taken together with the carbon atom to which they are attached form an optionally substituted C₃-C₆ cycloalkyl, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of Formula I, and Intermediates of the Disclosure are compounds of Formula II, wherein E-1 is E-1-1; and R^1a and R^1b taken together with the carbon atom to which they are attached form an optionally substituted 4- to 6-membered optionally substituted heterocyclo, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of Formula I, and Intermediates of the Disclosure are compounds of Formula II, wherein E-1 is E-1-1, R^1a and R^1b are hydrogen, and, q, r, s, and t are 1, or a pharmaceutically acceptable salt or solvate thereof, i.e., E-1-1 is E-1-1-A:

In another embodiment, Compounds of the Disclosure are compounds of Formula I, and Intermediates of the Disclosure are compounds of Formula II, wherein E-1 is E-1-1, R^1a and R^1b are hydrogen, and q is 2; r is 1; s is 0; and t is 1, or a pharmaceutically acceptable salt or solvate thereof, i.e., E-1-1 is E-1-1-B:

In another embodiment, Compounds of the Disclosure are compounds of Formula I, and Intermediates of the Disclosure are compounds of Formula II, wherein E-1 is E-1-1, R^1a and R^1b are hydrogen, and q is 1; r is 0; s is 0; and t is 2, or a pharmaceutically acceptable salt or solvate thereof, i.e., E-1-1 is E-1-1-C:

In another embodiment, Compounds of the Disclosure are compounds of Formula I, and Intermediates of the Disclosure are compounds of Formula II, wherein E-1 is E-1-1, R^1a and R^1b are hydrogen, and q is 0; r is 1; s is 1; and t is 1, or a pharmaceutically acceptable salt or solvate thereof, i.e., E-1-1 is E-1-1-D:

In another embodiment, Compounds of the Disclosure are compounds of Formula I, and Intermediates of the Disclosure are compounds of Formula II, wherein E-1 is E-1-1, R^1a and R^1b are hydrogen, and q is 1; r is 1; s is 0; and t is 1, or a pharmaceutically acceptable salt or solvate thereof, i.e., E-1-1 is E-1-1-E:

In another embodiment, Compounds of the Disclosure are compounds of Formula I, and Intermediates of the Disclosure are compounds of Formula II, wherein E-1 is E-1-1; and R^1a and R^1b are independently C₁-C₃ alkyl, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of Formula I, and Intermediates of the Disclosure are compounds of Formula II, wherein E 1 is E-1-1; and R^1a and R^1b are independently C₁-C₃ alkyl; and q, r, s, and t are 1, or a pharmaceutically acceptable salt or solvate thereof, i.e., E-1-1 is E-1-1-F:

In another embodiment, Compounds of the Disclosure are compounds of Formula I, and Intermediates of the Disclosure are compounds of Formula II, wherein E 1 is E-1-1; and R^1a and R^1b taken together with the carbon atom to which they are attached form an optionally substituted C₃-C₆ cycloalkyl; and q, r, s, and t are 1, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of Formula I, and Intermediates of the Disclosure are compounds of Formula II, wherein E-1 is E-1-1; R^1a is C₁-C₃ alkyl; and R^1b is hydrogen; and q, r, s, and t are 1, or a pharmaceutically acceptable salt or solvate thereof, i.e., E-1-1 is E-1-1-G:

In another embodiment, Compounds of the Disclosure are compounds of Formula III:

wherein R^1a, R^3a, Z¹, Z², X¹, A¹, X², L, and B¹ are as defined in connection with Formula I, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of Formula IV:

wherein R^1a, R^3a, Z¹, Z², X¹, A¹, X², L, and B¹ are as defined in connection with Formula I, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of Formula I, and Intermediates of the Disclosure are compounds of Formula II, wherein E 1 is E-1-1; and R^1a and R^1b taken together with the carbon atom to which they are attached form an —C(═O)— group, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of Formula I, and Intermediates of the Disclosure are compounds of Formula II, wherein E 1 is E-1-1; R^1a and R^1b taken together with the carbon atom to which they are attached form an —C(═O)— group; and q, r, s, and t are 1, or a pharmaceutically acceptable salt or solvate thereof, i.e., E-1-1 is E-1-1-H:

In another embodiment, Compounds of the Disclosure are compounds of Formula I, and Intermediates of the Disclosure are compounds of Formula II, wherein:

E-1 is E-1-2;

R^1c is C₁-C₃ alkyl;

R^1d is selected from the group consisting of hydrogen and C₁-C₃ alkyl; or

R^1c and R^1d taken together with the carbon atom to which they are attached form an —C(═O)— group, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of Formula I, and Intermediates of the Disclosure are compounds of Formula II, E-1 is E-1-2; R^1c is C₁-C₃ alkyl; and R^1d is selected from the group consisting of hydrogen and C₁-C₃ alkyl, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R^1d is hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of Formula V:

wherein R^1c, R^3a, Z¹, Z², X¹, A¹, X², L, and B¹ are as defined in connection with Formula I, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of Formula VI:

wherein R^1c, R^3a, Z¹, Z², X¹, A¹, X², L, and B¹ are as defined in connection with Formula I, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of Formula I, and Intermediates of the Disclosure are compounds of Formula II, wherein E-1 is E-1-2; and R^1c and R^1d taken together with the carbon atom to which they are attached form an —C(═O)— group, or a pharmaceutically acceptable salt or solvate thereof, i.e., E-1-2 is E-1-2-A:

In another embodiment, Compounds of the Disclosure are compounds of Formula I, and Intermediates of the Disclosure are compounds of Formula II, wherein E is E-2, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, E-2 is:

In another embodiment, Compounds of the Disclosure are compounds of Formula I, and Intermediates of the Disclosure are compounds of Formula II, wherein E is E-3, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, E-3 is:

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VI, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, below, wherein X¹ is —C(═O)—, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VI, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, wherein X¹ is —S(═O)₂—, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VI, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, wherein X¹ is —CR^4aR^4b—, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R^4a and R^4b are hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VI, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, wherein X¹ is absent, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VI, XV, or XVI, see below, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, wherein:

A¹ is selected from the group consisting of:

wherein the bond designated with an “*” is attached to X²;

R^5a, R^5b, R^5c and R^5d are each independently selected from the group consisting of hydrogen, halo, C₁-C₃ alkyl, and C₁-C₃ alkoxy;

e is 0, 1, or 2; and

f is 0, 1, or 2, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VI, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, wherein A¹ is A¹-1, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R^5a, R^5b, R^5c, and R^5d are hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VI, XV, or XVI, below, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, wherein A¹ is A¹-2, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R^5a, R^5b, R^5c, and R^5d are hydrogen. In another embodiment, R^5a is fluoro or chloro; and R^5b, R^5c, and R^5d are hydrogen. In another embodiment, R^5b is fluoro or chloro; and R^5a, R^5c, and R^5d are hydrogen. In another embodiment, R^5c is fluoro or chloro; and R^5a, R^5b, and R^5d are hydrogen. In another embodiment, R^5d is fluoro or chloro; and R^5a, R^5b, and R^5c are hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VI, XV, or XVI, below, wherein A¹ is A¹-3, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R^5a, R^5b, and R^5d are hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VI, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, wherein A¹ is A¹-4, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R^5a and R^5b are hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VI, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, wherein A¹ is A¹-5, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VI, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, wherein A¹ is A¹-6, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VI, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, wherein A¹ is A¹-7, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VI, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, wherein A¹ is A¹-8, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R^5a, R^5b, and R^5c are hydrogen. In another embodiment, e is 0 or 1; and f is 0 or 1.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VI, XV, or XVI, below, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, wherein A¹ is A¹-9, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R^5a, R^5c, and R^5d are hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VI, XV, or XVI, below, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, wherein A¹ is A¹-10, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R^5a and R^5d are hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VI, XV, or XVI, below, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, wherein A¹ is A¹-11, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R^5a and R^5b are hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VI, XV or XVI, below, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, wherein A¹ is A¹-12, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R^5a and R^5b are hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VI, XV or XVI, below, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, wherein A¹ is A¹-13, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R^5a and R^5b are hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VI, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, wherein X² is —C(═O)—, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VI, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, wherein X² is —S(═O)₂—, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VI, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, wherein X² is —O—, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VI, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, wherein X² is —CR^4cR^4d—, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R^4c and R^4d are hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VI, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, wherein X² is absent, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of Formula VII:

wherein R^1a, R^3a, Z¹, Z², R^5a, R^5b, R^5c, R^5d, J¹, J⁴, J⁵, and B¹ are as defined in connection with Formula I, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of Formula VII, wherein R^1a is selected from the group consisting of hydrogen and C₁-C₃ alkyl, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R^1a is methyl or ethyl. In another embodiment, Compounds of the Disclosure are compounds of Formula VII, wherein R^1a is methyl.

In another embodiment, Compounds of the Disclosure are compounds of Formula VII, wherein R^3a is selected from the group consisting of halo and C₁-C₄ haloalkyl, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of Formula VII, wherein R^5a, R^5b, R^5c, and R^5d are each independently selected from the group consisting of hydrogen and halo, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, R^5a, R^5b, R^5c, and R^5d are each hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of Formula VII, wherein Z¹ and Z² are —C(H)═, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VII, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, J¹ is cycloalkylenyl, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, J¹ is a C₄-C₆ cycloalkylenyl.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VII, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, wherein J¹ is heterocyclenyl, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, J¹ is selected from the group consisting of:

or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VI, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, wherein J¹ is absent, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VI, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, wherein J² is selected from the group consisting of —(CH₂)_m1— and —C≡C—; and m1 is 0, 1, or 2, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, J² is —(CH₂)_m1—; and m1 is 0. In another embodiment, J² is —(CH₂)_m1—; and m1 is 1. In another embodiment, J² is —C≡C—.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VI, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, wherein J³ is selected from the group consisting of cycloalkylenyl and heterocyclenyl, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, J³ is a C₄-C₆ cycloalkylenyl. In another embodiment, J³ is a 4- to 10-membered heterocyclenyl.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I-VI, wherein J³ is absent, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VII, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, wherein J⁴ is selected from the group consisting of alkylenyl, cycloalkylenyl, and heterocyclenyl, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, J⁴ is a C₁-C₆ alkylenyl. In another embodiment, J⁴ is a C₄-C₆ cycloalkylenyl. In another embodiment, J⁴ is a 4- to 10-membered heterocyclenyl

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VII, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, wherein J⁴ is absent, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VII, and Intermediates of the Disclosure are compounds of Formula II or IX-XII, wherein J⁵ is selected from the group consisting of —(CH₂)_m2—, —O—, —N(H)—, and —C(═O)—; m2 is 0 or 1, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, J⁵ is —(CH₂)_m2— and m2 is 0.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VI, wherein:

X¹ is absent;

A¹ is selected from the group consisting phenylenyl and 6-membered heteroarylenyl;

X² is —C(═O)—;

L is selected from the group consisting of:

wherein the bond designated with an “*” is attached to X²; and

B¹ is B¹-2, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VII, or XV, below, wherein B¹ is B¹-1. In another embodiment, R⁸ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VII, or XV, below, wherein B¹ is B¹-2. In another embodiment, R⁸ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VII, or XV, below, wherein B¹ is B¹-3. In another embodiment, R⁸ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VII, or XV, below, wherein B¹ is B¹-4. In another embodiment, R⁸ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VII, or XVI, below, wherein B¹ is B¹-5. In another embodiment, R⁸ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VII, or XVI, below, wherein B¹ is B¹-6. In another embodiment, R⁸ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VII, or XVI, below, wherein B¹ is B¹-7. In another embodiment, R⁸ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VII, or XVI, below, wherein B¹ is B¹-9. In another embodiment, R⁸ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VII, or XVI, below, wherein B¹ is B¹-10. In another embodiment, R⁸ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VII, or XVI, below, wherein B¹ is B¹-11. In another embodiment, R⁸ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VII, or XVI, below, wherein B¹ is B¹-12. In another embodiment, R⁸ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VII, or XVI, below, wherein B¹ is B¹-13. In another embodiment, R⁸ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VII, or XVI, below, wherein B¹ is B¹-14. In another embodiment, R⁸ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VII, or XV, below, wherein B¹ is B¹-15. In another embodiment, R⁸ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VII, or XV, below, wherein B¹ is B¹-16. In another embodiment, R⁸ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VII, or XV, below, wherein B¹ is B¹-17. In another embodiment, R⁸ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VII, or XV, below, wherein B¹ is B¹-18. In another embodiment, R⁸ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VII, or XV, below, wherein B¹ is B¹-19. In another embodiment, R⁸ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VII, or XV, below, wherein B¹ is B¹-20. In another embodiment, R⁸ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VII, or XV, below, wherein B¹ is B¹-21. In another embodiment, R⁸ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VII, or XV, below, wherein B¹ is B¹-22. In another embodiment, R⁸ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VII, or XV, below, wherein B¹ is B¹-23. In another embodiment, R⁸ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VII, or XV, below, wherein B¹ is B¹-24. In another embodiment, R⁸ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VII, or XV, below, wherein B¹ is B¹-25. In another embodiment, R⁸ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VII, or XV, below, wherein B¹ is B¹-26. In another embodiment, R⁸ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VII, or XVI, below, wherein B¹ is B¹-27. In another embodiment, R⁸ is hydrogen. In another embodiment, R^2f is hydrogen. In another embodiment, R^2g is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I, III-VII, or XVI, below, wherein B¹ is B¹-28. In another embodiment, R⁸ is hydrogen. In another embodiment, R^2f is hydrogen. In another embodiment, R^2g is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VII, wherein:

J⁵ is selected from the group consisting of —O— and —N(H)—; and

B¹ is selected from the group consisting of hydrogen, B¹-1, B¹-2, B¹-3, and B¹-4, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, B¹ is B¹-1. In another embodiment, B¹ is B¹-2. In another embodiment, B¹ is B¹-3. In another embodiment, B¹ is B¹-1. In another embodiment, Z is —CH₂—. In another embodiment, Z is —C(═O)—. In another embodiment, R^2a, R^2b, and R^2c are independently selected from the group consisting of hydrogen and fluoro. In another embodiment, R³ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VII, wherein:

J⁵ is selected from the group consisting of —(CH₂)_m2— and —O—;

m2 is 0;

J⁴ is selected from the group consisting of:

wherein the bond designated with an “*” is attached to B¹;

R⁷ is selected from the group consisting of hydrogen, halo, cyano, hydroxy, C₁-C₃ alkyl, and C₁-C₃ alkoxy; and

B¹ is selected from the group consisting of B¹-1, B¹-2, B¹-3, and B¹-4, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, B¹ is B¹-1. In another embodiment, B¹ is B¹-2. In another embodiment, B¹ is B¹-3. In another embodiment, B¹ is B¹-1. In another embodiment, Z is —CH₂—. In another embodiment, Z is —C(═O)—. In another embodiment, R^2a, R^2b, and R^2c are independently selected from the group consisting of hydrogen and fluoro. In another embodiment, R³ is hydrogen. In another embodiment, J⁵ is —(CH₂)_m2— and m2 is 0.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VII, wherein:

J⁵ is —(CH₂)_m2—;

m2 is 0;

J⁴ is selected from the group consisting of:

wherein the bond designated with an “*” is attached to B¹;

R⁷ is selected from the group consisting of hydrogen, halo, cyano, hydroxy, C₁-C₃ alkyl, and C₁-C₃ alkoxy; and

B¹ is selected from the group consisting of B¹-15, B¹-16, B¹-17, B¹-18, B¹-19, and B¹-20, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, B¹ is B¹-15. In another embodiment, B¹ is B¹-16. In another embodiment, B¹ is B¹-17. In another embodiment, B¹ is B¹-18. In another embodiment, B¹ is B¹-19. In another embodiment, B¹ is B¹-20. In another embodiment, Z is —CH₂—. In another embodiment, Z is —C(═O)—. In another embodiment, R^2b and R^2c are independently selected from the group consisting of hydrogen and fluoro. In another embodiment, R³ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VII, wherein:

J⁵ is —(CH₂)_m2—;

m2 is 0;

J⁴ is selected from the group consisting of:

wherein the bond designated with an “*” is attached to B¹;

R⁷ is selected from the group consisting of hydrogen, halo, cyano, hydroxy, C₁-C₃ alkyl, and C₁-C₃ alkoxy; and

B¹ is selected from the group consisting of B¹-21, B¹-22, B¹-23, B¹-24, B¹-25, and B¹-26, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, B¹ is B¹-21. In another embodiment, B¹ is B¹-22. In another embodiment, B¹ is B¹-23. In another embodiment, B¹ is B¹-24. In another embodiment, B¹ is B¹-25. In another embodiment, B¹ is B¹-26. In another embodiment, R^2b and R^2c are independently selected from the group consisting of hydrogen and fluoro. In another embodiment, R³ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VII, wherein:

J⁵ is selected from the group consisting of —(CH₂)_m2— and —C(═O)—;

m2 is 0, 1, 2, or 3; and

B¹ is selected from the group consisting of B¹-5, B¹-6, and B¹-7, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, B¹ is B¹-5. In another embodiment, B¹ is B¹-6. In another embodiment, B¹ is B¹-7. In another embodiment, Z is —CH₂—. In another embodiment, Z is —C(═O)—. In another embodiment, m is 1 or 2; and n is 1 or 2. In another embodiment, R^2d and R^2e are independently selected from the group consisting of hydrogen and fluoro. In another embodiment, R³ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VII, wherein:

J⁵ is selected from the group consisting of —(CH₂)_m2— and —C(═O)—;

m2 is 0, 1, 2, or 3; and

B¹ is selected from the group consisting of B¹-27 and B¹-28, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, B¹ is B¹-27. In another embodiment, B¹ is B¹-28. In another embodiment, Z is —CH₂—. In another embodiment, Z is —C(═O)—. In another embodiment, R^2d and R^2e are independently selected from the group consisting of hydrogen and fluoro. In another embodiment, R^2d and R^2e are independently selected from the group consisting of hydrogen and fluoro. In another embodiment, R^2e and R^2f are independently selected from the group consisting of hydrogen and fluoro. In another embodiment, R^2e and R^2f are hydrogen. In another embodiment, R³ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VII, wherein:

J⁵ is selected from the group consisting of —(CH₂)_m2— and —C(═O)—;

m2 is 0, 1, 2, or 3; and

B¹ is selected from the group consisting of B¹-9, B¹-10, and B¹-11, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, B¹ is B¹-9. In another embodiment, B¹ is B¹-10. In another embodiment, B¹ is B¹-11. In another embodiment, Z is —CH₂—. In another embodiment, Z is —C(═O)—. In another embodiment, m is 1 or 2; and n is 1 or 2. In another embodiment, o is 1 or 2; and p is 1 or 2. In another embodiment, R^2d and R^2e are independently selected from the group consisting of hydrogen and fluoro. In another embodiment, R³ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VII, wherein:

J⁵ is selected from the group consisting of —(CH₂)_m2— and —C(═O)—;

m2 is 0, 1, 2, or 3; and

B¹ is selected from the group consisting of B¹-12, B¹-13, and B¹-14, or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, B¹ is B¹-12. In another embodiment, B¹ is B¹-13. In another embodiment, B¹ is B¹-14. In another embodiment, Z is —CH₂—. In another embodiment, Z is —C(═O)—. In another embodiment, m is 1 or 2; and n is 1 or 2. In another embodiment, R^2d and R^2e are independently selected from the group consisting of hydrogen and fluoro. In another embodiment, R³ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of Formula XV:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R^1a is selected from the group consisting of hydrogen and C₁-C₃ alkyl;

A¹ is selected from the group consisting of A¹-2, A¹-3, A¹-9, A¹-10, A¹-11, A¹-12, and A¹-13;

Z³ and Z⁴ are independently selected from the group consisting of N and CH;

with the provisos that (i) at least one of Z³ or Z⁴ is CH; and (ii) y¹ and w¹ are 1 when Z⁴ is N;

y, y¹, w, and w¹ are each independently 0 or 1;

m2 is 0 or 1; and

B¹ is selected from the group consisting of B¹-1, B¹-2, B¹-3, B¹-4, B¹-15, B¹-16, B¹-17, B¹-18, B¹-19, B¹-20, B¹-21, B¹-22, B¹-23, B¹-24, B¹-25 and B¹-26.

In another embodiment, Compounds of the Disclosure are compounds of Formula XV, or a pharmaceutically acceptable salt or solvate thereof, wherein R^1a is methyl.

In another embodiment, Compounds of the Disclosure are compounds of Formula XV, or a pharmaceutically acceptable salt or solvate thereof, wherein y is 0 and w is 0.

In another embodiment, Compounds of the Disclosure are compounds of Formula XV, or a pharmaceutically acceptable salt or solvate thereof, wherein y is 0 and w is 1.

In another embodiment, Compounds of the Disclosure are compounds of Formula XV, or a pharmaceutically acceptable salt or solvate thereof, wherein y is 1 and w is 1.

In another embodiment, Compounds of the Disclosure are compounds of Formula XV, or a pharmaceutically acceptable salt or solvate thereof, wherein Z⁴ is CH, y¹ is 0, and w¹ is 0.

In another embodiment, Compounds of the Disclosure are compounds of Formula XV, or a pharmaceutically acceptable salt or solvate thereof, wherein Z⁴ is CH, y¹ is 0, and w¹ is 1.

In another embodiment, Compounds of the Disclosure are compounds of Formula XV, or a pharmaceutically acceptable salt or solvate thereof, wherein y¹ is 1 and w¹ is 1.

In another embodiment, Compounds of the Disclosure are compounds of Formula XV, or a pharmaceutically acceptable salt or solvate thereof, wherein m2 is 0.

In another embodiment, Compounds of the Disclosure are compounds of Formula XV, or a pharmaceutically acceptable salt or solvate thereof, wherein m2 is 1.

In another embodiment, Compounds of the Disclosure are compounds of Formula XVI:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R^1a is selected from the group consisting of hydrogen and C₁-C₃ alkyl;

A¹ is selected from the group consisting of A¹-2, A¹-3, A¹-9, A¹-10, A¹-11, A¹-12, and A¹-13;

y² and w² are each independently 0 or 1;

m4 is 0 or 1; and

B¹ is selected from the group consisting of B¹-5, B¹-6, B¹-7, B¹-9, B¹-10, B¹-11, B¹-12, B¹-13, B¹-14, B¹-27, and B¹-28.

In another embodiment, Compounds of the Disclosure are compounds of Formula XVI, or a pharmaceutically acceptable salt or solvate thereof, wherein R^1a is methyl.

In another embodiment, Compounds of the Disclosure are compounds of Formula XVI, or a pharmaceutically acceptable salt or solvate thereof, wherein y² is 0 and w² is 0.

In another embodiment, Compounds of the Disclosure are compounds of Formula XVI, or a pharmaceutically acceptable salt or solvate thereof, wherein y² is 1 and w² is 0.

In another embodiment, Compounds of the Disclosure are compounds of Formula XVI, or a pharmaceutically acceptable salt or solvate thereof, wherein y² is 1 and w² is 1.

In another embodiment, Compounds of the Disclosure are compounds of Formula XVI, or a pharmaceutically acceptable salt or solvate thereof, wherein m4 is 0.

In another embodiment, Compounds of the Disclosure are compounds of Formula XVI, or a pharmaceutically acceptable salt or solvate thereof, wherein m4 is 1.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VII, wherein B¹ is selected from the group consisting of:

or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of Formula XV, wherein B¹ is selected from the group consisting of:

or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of Formula XVI, wherein B¹ is selected from the group consisting of:

or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VII, wherein R^3a is halo, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VII, wherein R^3a is C₁-C₄ alkyl, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VII, wherein R^3a is C₁-C₄ haloalkyl, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VII, wherein R^3a is selected from the group consisting of —Cl, —CH₃, and —CF₃, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VII, wherein Z¹ is —C(H)═, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of any one of Formulae I or III-VII, wherein Z² is —C(H)═, or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment, Compounds of the Disclosure are compounds of Formula VIII:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R^1a is selected from the group consisting of hydrogen and C₁-C₃ alkyl;

R^2d and R^2e are each independently selected from the group consisting of hydrogen and halo;

R^5a, R^5b, R^5c and R^5d are each independently selected from the group consisting of hydrogen and halo;

w and y are independently 0 or 1;

m1 is 0 or 1; and

Z is selected from the group consisting of —CH₂— and —C(═O)—.

In another embodiment, Compounds of the Disclosure are compounds of Formula VIII, or a pharmaceutically acceptable salt or solvate thereof, wherein R^1a is methyl.

In another embodiment, Compounds of the Disclosure are compounds of Formula VIII, or a pharmaceutically acceptable salt or solvate thereof, wherein R^2d and R^2e are hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of Formula VIII, or a pharmaceutically acceptable salt or solvate thereof, wherein R^5a, R^5b, R^5c, and R^5d are hydrogen.

In another embodiment, Compounds of the Disclosure are compounds of Formula VIII, or a pharmaceutically acceptable salt or solvate thereof, wherein R^5b, R^5c, and R^5d are hydrogen; and R^5a is halo.

In another embodiment, Compounds of the Disclosure are compounds of Formula VIII, or a pharmaceutically acceptable salt or solvate thereof, wherein R^5a, R^5b, R^5c are hydrogen; and R^5d is halo.

In another embodiment, Compounds of the Disclosure are compounds of Formula VIII, or a pharmaceutically acceptable salt or solvate thereof, wherein m1 is 0.

In another embodiment, Compounds of the Disclosure are compounds of Formula VIII, or a pharmaceutically acceptable salt or solvate thereof, wherein m1 is 1.

In another embodiment, Compounds of the Disclosure are compounds of Formula VIII, or a pharmaceutically acceptable salt or solvate thereof, wherein w and y are 0.

In another embodiment, Compounds of the Disclosure are compounds of Formula VIII, or a pharmaceutically acceptable salt or solvate thereof, wherein w and y are 1.

In another embodiment, Compounds of the Disclosure are compounds of Formula VIII, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is —C(═O)—.

In another embodiment, Compounds of the Disclosure are any one or more of the compounds of Table 1, or a pharmaceutically acceptable salt or solvate thereof.

TABLE 1
Cpd.
No. Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
252
253
254
255
256
257
258
259
260
261
262
263
264
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
286
287
288
289
290
291
292
293
294
295
296
297
298
299
300
301
302
303
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
327
328
329
330
331
332
333
334
335
336
337
338
339
340
341
342
343
344
345
346
347
348
349
350
351
352
353
354
355
356
357
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
375
376
377
378
379
380
381
382
383
384
385
386
387
388
389
390
391
392
393
394
395
396
397
398
399
400
401
402
403
404
405
406
407
408
409
410
411
412
413
414
415
416
417
418
419
420
421
422
423
424
425
426
427
428
429
430
431
432
433
434
435
436
437
438
439
440
441
442
443
444
445
446
447
448
449
450
451
452
453
454
455
456
457
458
459
460
461
462
463
467
468
469
470
471
472
473
474
475
476
477
478
479
480
481
482
483
484
485
486
487
488
489
490
491
492
493
494
495
496
497
498
499
500
501
502
503
504
505
506
507
508
509
510
511
512
513
514
515
516
517
518
519
520
521
522
523
524
525
526
527
528
529
530
531
532
533
534
535
536
537
538
539
540
541
542
543
544
545
546
547
548
549
550
551
552
553
554
555
556
557
558
559
560
561
562
563
564
565
566
567
568
569
570
571
572
573
574
575
576
577
578
579
580
581
582
583
584
585
586
587
588

In another embodiment, the disclosure provides a pharmaceutical composition comprising a Compound of the Disclosure and a pharmaceutically acceptable carrier or excipient.

Compounds of the Disclosure contain an asymmetric carbon atom. In some embodiments, Compounds of the Disclosure are racemic compounds. In other embodiments, Compounds of the Disclosure are enantiomerically enriched, e.g., the enantiomeric excess or “ee” of the compound is about 5% or more as measured by chiral HPLC. In another embodiment, the ee is about 10%. In another embodiment, the ee is about 20%. In another embodiment, the ee is about 30%. In another embodiment, the ee is about 40%. In another embodiment, the ee is about 50%. In another embodiment, the ee is about 60%. In another embodiment, the ee is about 70%. In another embodiment, the ee is about 80%. In another embodiment, the ee is about 85%. In another embodiment, the ee is about 90%. In another embodiment, the ee is about 91%. In another embodiment, the ee is about 92%. In another embodiment, the ee is about 93%. In another embodiment, the ee is about 94%. In another embodiment, the ee is about 95%. In another embodiment, the ee is about 96%. In another embodiment, the ee is about 97%. In another embodiment, the ee is about 98%. In another embodiment, the ee is about 99%.

In another embodiment, the cereblon binding portion of a Compound of the Disclosure, e.g., B¹ is B¹-1, B¹-2, B¹-3, B¹-4, B¹-5, B¹-6, or B¹-7, is enantiomerically enriched. In another embodiment, the cereblon binding portion of the molecule is racemic. The present disclosure encompasses all possible stereoisomeric, e.g., diastereomeric, forms of Compounds of the Disclosure. For example, all possible stereoisomers of Compounds of the Disclosure are encompassed when E portion of Formula I is enantiomerically enriched and the cereblon binding portion of the molecule is racemic. When a Compound of the Disclosure is desired as a single enantiomer, it can be obtained either by resolution of the final product or by stereospecific synthesis from either isomerically pure starting material or use of a chiral auxiliary reagent, for example, see Z. Ma et al., Tetrahedron: Asymmetry, 8(6), pages 883-888 (1997). Resolution of the final product, an intermediate, or a starting material can be achieved by any suitable method known in the art. Additionally, in situations where tautomers of the Compounds of the Disclosure are possible, the present disclosure is intended to include all tautomeric forms of the compounds.

The present disclosure encompasses the preparation and use of salts of Compounds of the Disclosure, including pharmaceutically acceptable salts. As used herein, the “pharmaceutically acceptable salt” refers to non-toxic salt forms of Compounds of the Disclosure. See e.g., Gupta et al., Molecules 23:1719 (2018). Salts of Compounds of the Disclosure can be prepared during the final isolation and purification of the compounds or separately by reacting the compound with an acid having a suitable cation. The pharmaceutically acceptable salts of Compounds of the Disclosure can be acid addition salts formed with pharmaceutically acceptable acids. Examples of acids which can be employed to form pharmaceutically acceptable salts include inorganic acids such as nitric, boric, hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Nonlimiting examples of salts of compounds of the disclosure include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethansulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerolphosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, paratoluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedisulfonate, benzene sulfonate, and p-toluenesulfonate salts. In addition, available amino groups present in the compounds of the disclosure can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. In light of the foregoing, any reference Compounds of the Disclosure appearing herein is intended to include the actual compound as well as pharmaceutically acceptable salts, hydrates, or solvates thereof.

The present disclosure also encompasses the preparation and use of solvates of Compounds of the Disclosure. Solvates typically do not significantly alter the physiological activity or toxicity of the compounds, and as such may function as pharmacological equivalents. The term “solvate” as used herein is a combination, physical association and/or solvation of a compound of the present disclosure with a solvent molecule such as, e.g. a disolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to compound of the present disclosure is about 2:1, about 1:1 or about 1:2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, “solvate” encompasses both solution-phase and isolatable solvates. Compounds of the Disclosure can be present as solvated forms with a pharmaceutically acceptable solvent, such as water, methanol, and ethanol, and it is intended that the disclosure includes both solvated and unsolvated forms of Compounds of the Disclosure. One type of solvate is a hydrate. A “hydrate” relates to a particular subgroup of solvates where the solvent molecule is water. Solvates typically can function as pharmacological equivalents. Preparation of solvates is known in the art. See, for example, M. Caira et al, J. Pharmaceut. Sci., 93(3):601-611 (2004), which describes the preparation of solvates of fluconazole with ethyl acetate and with water. Similar preparation of solvates, hemisolvates, hydrates, and the like are described by E. C. van Tonder et al., AAPS Pharm. Sci. Tech., 5(1):Article 12 (2004), and A. L. Bingham et al., Chem. Commun. 603-604 (2001). A typical, non-limiting, process of preparing a solvate would involve dissolving a Compound of the Disclosure in a desired solvent (organic, water, or a mixture thereof) at temperatures above 20° C. to about 25° C., then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g., filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvent in a crystal of the solvate.

In another aspect, the present disclosure provides the following particular embodiments drawn to Compounds of the Disclosure, referred to as “CD Embodiment 1,” “CD Embodiment 2,” “CD Embodiment 3,” and so on.

CD Embodiment 1. A compound of Formula I, see above, wherein:

R^3a is selected from the group consisting of halo, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;

Z¹ is selected from the group consisting of ═C(H)— and ═N—;

Z² is selected from the group consisting of ═C(R^3b)— and ═N—;

R^3b is selected from the group consisting of hydrogen, halo, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;

E is a spiroheterocyclenyl;

X¹ is selected from the group consisting of —C(═O)—, —S(═O)₂—, and —CR^4aR^4b—; or

X¹ is absent;

R^4a and R^4b are independently selected from the group consisting of hydrogen and C₁-C₃ alkyl;

A¹ is selected from the group consisting of cycloalkylenyl, heterocyclenyl, phenylenyl, and heteroarylenyl;

X² is selected from the group consisting of —C(═O)—, —S(═O)₂—, —O—, and —CR^4cR^4d—; or

X² is absent;

R^4c and R^4d are independently selected from the group consisting of hydrogen and C_1-3 alkyl;

L is -J¹-J²-J³-J⁴-J⁵-,

wherein J₁ is attached to X²;

J¹ is selected from the group consisting of cycloalkylenyl and heterocyclenyl; or

J¹ is absent;

J² is selected from the group consisting of —(CH₂)_m1—, —CH═CH—, and —C≡C—;

m1 is 0, 1, 2, or 3;

J³ is selected from the group consisting of alkylenyl, heteroalkylenyl, cycloalkylenyl, heterocyclenyl, phenylenyl, and heteroarylenyl; or

J³ is absent;

J⁴ is selected from the group consisting of alkylenyl, cycloalkylenyl, and heterocyclenyl; or

J⁴ is absent;

J⁵ is selected from the group consisting of —(CH₂)_m2—, —O—, —N(R⁶)—, and —C(═O)—;

m2 is 0, 1, 2, or 3;

R⁶ is selected from the group consisting of hydrogen and C₁-C₃ alkyl;

B¹ is selected from the group consisting of B¹-1, B¹-2, B¹-3, B¹-4, B¹-5, B¹-6, B¹-7, B¹-9, B¹-10, B¹-1, B¹-12, B¹-13, B¹-14, B¹-15, B¹-16, B¹-17, B¹-18, B¹-19, B¹-20, B¹-21, B¹-22, B¹-23, B¹-24, B¹-25, and B¹-26, see above;

R^2a, R^2b, R^2c, R^2d, and R^2e are independently selected from the group consisting of hydrogen, halo, C₁-C₃ alkyl, and C₁-C₃ alkoxy; or

R³ is selected from the group consisting of hydrogen, deuterium, fluoro, and C₁-C₃alkyl;

m is 1, 2, or 3;

n is 1, 2, or 3;

o is 1, 2, or 3;

p is 1, 2, or 3;

Z is selected from the group consisting of —CR^1jR^1k— and —C(═O)—;

R^1j and R^1k are independently selected from the group consisting of hydrogen and C₁-C₃ alkyl; or R^1j and R^1k taken together with the carbon to which they are attached from a C₃-C₆ cycloalkyl, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 2. The compound of CD Embodiment 1, wherein E is selected from the group consisting of E-1, E-2, and E-3, see above;

wherein the bond designated with an “*” is attached to X¹;

o and p are independently 0 or 1;

q and r are independently 0, 1, 2, or 3;

wherein the sum of o, p, q, and r is 2, 3, 4, 5, 6, or 7;

s is 0, 1, 2, 3, or 4;

t, u, v, w, and x are independently 0, 1, 2, or 3;

R^1a and R^1b are independently selected from the group consisting of hydrogen, C₁-C₃ alkyl, C₁-C₄ haloalkyl, optionally substituted C₃-C₆ cycloalkyl, and (C₃-C₆ cycloalkyl)C₁-C₆ alkyl; or

R^1a and R^1b taken together with the carbon atom to which they are attached form an —C(═O)— group; or

R^1a and R^1b taken together with the carbon atom to which they are attached form an optionally substituted C₃-C₆ cycloalkyl; or

R^1a and R^1b taken together with the carbon atom to which they are attached form an optionally substituted 4- to 6-membered heterocyclo;

R^1c and R^1d are independently selected from the group consisting of hydrogen and C₁-C₃ alkyl; or

R^1c and R^1d taken together with the carbon atom to which they are attached form an —C(═O)— group;

each R^1f is independently C₁-C₃ alkyl;

j is 0, 1, 2, 3, or 4;

each R^1f is independently C₁-C₃ alkyl;

k is 0, 1, 2, 3, or 4;

each R^1g is independently C₁-C₃ alkyl; and

h is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 3. The compound of CD Embodiment 2, wherein E is E-1, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 4. The compound of CD Embodiment 3, wherein E-1 is selected from the group consisting of E-1-1 and E-1-2, see above, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 5. The compound of CD Embodiment 4, wherein E-1 is E-1-1, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 6. The compound of CD Embodiment 5, wherein R^1a and R^1b are hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 7. The compound of CD Embodiment 6, wherein q, r, s, and t are 1, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 8. The compound of CD Embodiment 6, wherein q is 2; r is 1; s is 0; and t is 1, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 9. The compound of CD Embodiment 6, wherein q is 1; r is 0; s is 0; and t is 2, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 10. The compound of CD Embodiment 6, wherein q is 0; r is 1; s is 1; and t is 1, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 11. The compound of CD Embodiment 6, wherein q is 1; r is 1; s is 0; and t is 1, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 12. The compound of CD Embodiment 5, wherein R^1a and R^1b are independently C₁-C₃ alkyl, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 13. The compound of CD Embodiment 12, wherein q, r, s, and t are 1, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 14. The compound of CD Embodiment 5, wherein R^1a is C₁-C₃ alkyl; and R^1b is hydrogen or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 15. The compound of CD Embodiment 14, wherein q, r, s, and t are 1, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 16. The compound of CD Embodiment 15 of Formula III, see above, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 17. The compound of CD Embodiment 15 of Formula IV, see above, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 18. The compound of CD Embodiment 5, wherein R^1a and R^1b taken together with the carbon atom to which they are attached form a —C(═O)— group, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 19. The compound of CD Embodiment 18, wherein q, r, s, and t are 1, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 20. The compound of CD Embodiment 4, wherein:

E-1 is E-1-2;

R^1c is C₁-C₃ alkyl;

R^1d is selected from the group consisting of hydrogen and C₁-C₃ alkyl; or

R^1c and R^1d taken together with the carbon atom to which they are attached form a —C(═O)— group, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 21. The compound of CD Embodiment 20, wherein R^1d is hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 22. The compound of CD Embodiment 21 of Formula V, see above, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 23. The compound of CD Embodiment 21 of Formula VI, see above, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 24. The compound of CD Embodiment 20, wherein R^1c and R^1d taken together with the carbon atom to which they are attached form a —C(═O)— group, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 25. The compound of CD Embodiment 2, wherein E is E-2, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 26. The compound of CD Embodiment 25, wherein E-2 is E-2-1, see above, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 27. The compound of CD Embodiment 2, wherein E is E-3, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 28. The compound of CD Embodiment 27, wherein E-3 is E-3-1, see above, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 29. The compound of any one of CD Embodiments 1-26, wherein X¹ is —C(═O)—, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 30. The compound of any one of CD Embodiments 1-26, wherein X¹ is —S(═O)₂—, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 31. The compound of any one of CD Embodiments 1-26, wherein X¹ is —CR^4aR^4b—, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 32. The compound of CD Embodiments 31, wherein R^4a and R^4b are hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 33. The compound of any one of CD Embodiments 1-28, wherein X¹ is absent, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 34. The compound of any one of CD Embodiments 1-33, wherein:

A¹ is selected from the group consisting of A¹-1, A¹-2, A¹-3, A¹-4, A¹-5, A¹-6, A¹-7, A¹-8, A¹-9, A¹-10, A¹-11, A¹-12, and A¹-13 see above, wherein the bond designated with an “*” is attached to X².

R^5a, R^5b, R^5c and R^5d are each independently selected from the group consisting of hydrogen, halo, C₁-C₃ alkyl, and C₁-C₃ alkoxy

e is 0, 1, or 2; and

f is 0, 1, or 2, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 35. The compound of CD Embodiment 34, wherein A¹ is A¹-1, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 36. The compound of CD Embodiment 34, wherein A¹ is A¹-2, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 37. The compound of CD Embodiment 34, wherein A¹ is A¹-3, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 38. The compound of CD Embodiment 34, wherein A¹ is A¹-4, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 39. The compound of CD Embodiment 34, wherein A¹ is A¹-5, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 40. The compound of CD Embodiment 34, wherein A¹ is A¹-6, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 41. The compound of CD Embodiment 34, wherein A¹ is A¹-7, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 42. The compound of any one of CD Embodiments 34-36, wherein R^5a, R^5b, R^5c, and R^5d are hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 43. The compound of any one of CD Embodiments 1-42, wherein X² is —C(═O)—, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 44. The compound of any one of CD Embodiments 1-42, wherein X² is —S(═O)₂—, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 45. The compound of any one of CD Embodiments 1-42, wherein X² is —O—, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 46. The compound of any one of CD Embodiments 1-42, wherein X² is —CR^4cR^4d—, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 47. The compound of CD Embodiment 46, wherein R^4c and R^4d are hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 48. The compound of any one of CD Embodiment 1-42, wherein X² is absent, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 49. The compound of any one of CD Embodiments 1-48, wherein J¹ is cycloalkylenyl, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 50. The compound of any one of CD Embodiments 1-48, wherein J¹ is heterocyclenyl, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 51. The compound of CD Embodiment 20, wherein J¹ is selected from the group consisting of J¹-1, J¹-2, J¹-3, J¹-4, J¹-5, J¹-6, J¹-7, J¹-8, J¹-9, J¹-10, J¹-11, J¹-12, and J¹-13, see above, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 52. The compound of CD Embodiment 51, wherein J¹ is J¹-1, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 53. The compound of CD Embodiment 51, wherein J¹ is J¹-2, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 54. The compound of CD Embodiment 51, wherein J¹ is J¹-3, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 55. The compound of CD Embodiment 51, wherein J¹ is J¹-4, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 56. The compound of CD Embodiment 51, wherein J¹ is J¹-5, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 57. The compound of CD Embodiment 51, wherein J¹ is J¹-6, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 58. The compound of CD Embodiment 51, wherein J¹ is J¹-7, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 59. The compound of CD Embodiment 51, wherein J¹ is J¹-8, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 60. The compound of CD Embodiment 51, wherein J¹ is J¹-9, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 61. The compound of CD Embodiment 51, wherein J¹ is J¹-10, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 62. The compound of CD Embodiment 51, wherein J¹ is J¹-11, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 63. The compound of CD Embodiment 51, wherein J¹ is J¹-12, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 64. The compound of CD Embodiment 51, wherein J¹ is J¹-13, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 65. The compound of any one of CD Embodiments, 1-48, wherein J¹ is absent, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 66. The compound of any one of CD Embodiments 1-65, wherein J² is selected from the group consisting of —(CH₂)_m1— and —C≡C—; and m1 is 0, 1, or 2, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 67. The compound of CD Embodiment 66, wherein J² is —(CH₂)_m1—; and m1 is 0, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 68. The compound of CD Embodiment 66, wherein J² is —(CH₂)_m1—; and m1 is 1, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 69. The compound of CD Embodiment 66, wherein J² is —C≡C—, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 70. The compound of any one of CD Embodiments 1-69, wherein J³ is selected from the group consisting of cycloalkylenyl and heterocyclenyl, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 71. The compound of CD Embodiment 70, wherein J³ is cycloalkylenyl, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 72. The compound of CD Embodiment 70, wherein J³ is heterocyclenyl, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 73. The compound of any one of CD Embodiments 1-69, wherein J³ is absent, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 74. The compound of any one of CD Embodiments 1-73, wherein J⁴ is selected from the group consisting of alkylenyl, cycloalkylenyl, and heterocyclenyl, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 75. The compound of CD Embodiment 74, wherein J⁴ is alkylenyl, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 76. The compound of CD Embodiment 74, wherein J⁴ is cycloalkylenyl, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 77. The compound of CD Embodiment 74, wherein J⁴ is heterocyclenyl, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 78. The compound of any one of CD Embodiments 1-73, wherein J⁴ is absent, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 79. The compound of any one of CD Embodiments 1-78, wherein:

J⁵ is selected from the group consisting of —O— and —N(H)—; and

B¹ is selected from the group consisting of B¹-1, B¹-2, B¹-3, and B¹-4, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 80. The compound of any one of CD Embodiments 1-77, wherein:

J⁵ is selected from the group consisting of —(CH₂)_m2— and —O—;

m2 is 0;

J⁴ is selected from the group consisting of J⁴-1, J⁴-2, J⁴-3, J⁴-4, J⁴-5, and J⁴-6, see above, wherein the bond designated with an “*” is attached to B¹;

R⁷ is selected from the group consisting of hydrogen, halo, cyano, hydroxy, C₁-C₃ alkyl, and C₁-C₃ alkoxy; and

B¹ is selected from the group consisting of B¹-1, B¹-2, B¹-3, and B¹-4, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 81. The compound of CD Embodiment 80, wherein J⁴ is J⁴-1, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 82. The compound of CD Embodiment 80, wherein J⁴ is J⁴-2, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 83. The compound of CD Embodiment 80, wherein J⁴ is J⁴-3, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 84. The compound of CD Embodiment 80, wherein J⁴ is J⁴-4, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 85. The compound of CD Embodiment 80, wherein J⁴ is J⁴-5, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 86. The compound of CD Embodiment 80, wherein J⁴ is J⁴-6, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 87. The compound of any one of CD Embodiments 79-86, wherein B¹ is B¹-1, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 88. The compound of CD Embodiment 87, wherein Z is —CH₂—, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 89. The compound of CD Embodiment 87, wherein Z is —C(═O)—, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 90. The compound of any one of CD Embodiments 79-86, wherein B¹ is B¹-2, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 91. The compound of CD Embodiment 90, wherein Z is —CH₂—, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 92. The compound of CD Embodiment 90, wherein Z is —C(═O)—, or a pharmaceutically acceptable salt or solvate thereof

CD Embodiment 93. The compound of any one of CD Embodiments 79-86, wherein B¹ is B¹-3, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 94. The compound of any one of CD Embodiments 79-86, wherein B¹ is B¹-4, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 95. The compound of any one of CD Embodiments 79-94, wherein R^2a, R^2b, and R^2c are independently selected from the group consisting of hydrogen and fluoro, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 96. The compound of CD Embodiment 95, wherein R^2a, R^2b, and R^2c are hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 97. The compound of any one of CD Embodiments 1-78, wherein:

J⁵ is selected from the group consisting of —(CH₂)_m2— and —C(═O)—;

m2 is 0, 1, 2, or 3; and

B¹ is selected from the group consisting of B¹-5, B¹-6, B¹-7, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 98. The compound of CD Embodiment 97, wherein B¹ is B¹-5, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 99. The compound of CD Embodiment 98, wherein Z is —CH₂—, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 100. The compound of CD Embodiment 98, wherein Z is —C(═O)—, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 101. The compound of any one of CD Embodiments 98-100, wherein m is 1 or 2; and n is 1, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 102. The compound of CD Embodiment 97, wherein B¹ is B¹-6, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 103. The compound of CD Embodiment 102, wherein Z is —CH₂—, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 104. The compound of CD Embodiment 102, wherein Z is —C(═O)—, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 105. The compound of any one of CD Embodiment 102-104, wherein m is 1 or 2; and n is 1 or 2, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 106. The compound of CD Embodiment 97, wherein B¹ is B¹-7, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 107. The compound of CD Embodiment 106, wherein m is 1 or 2; and n is 1 or 2, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 108. The compound of any one of CD Embodiments 97-107, wherein R^2d and R^2e are independently selected from the group consisting of hydrogen and fluoro, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 109. The compound of CD Embodiment 108, wherein R^2d and R^2e are hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 110. The compound of any one of CD Embodiments 79-108, wherein R³ is hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 111. The compound of any one of CD Embodiments 1-110, wherein R^3a is halo, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 112. The compound of any one of CD Embodiments 1-110, wherein R^3a is C₁-C₄ alkyl, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 113. The compound of any one of CD Embodiments 1-110, wherein R^3a is C₁-C₄ haloalkyl, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 114 The compound of any one of CD Embodiments 1-110, wherein R^3a is selected from the group consisting of —Cl, —CH₃, and —CF₃, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 115. The compound of any one of CD Embodiments 1-114, wherein Z¹ is —C(H)═, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 116. The compound of any one of CD Embodiment 1-115, wherein Z² is —C(H)═, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 117. The compound of CD Embodiment 1 that is any one or more of the compounds of Table 1, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 118. The compound of CD Embodiment 34, wherein A¹ is A¹-8, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 119. The compound of CD Embodiment 34, wherein A¹ is A¹-9, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 120. The compound of CD Embodiment 34, wherein A¹ is A¹-10, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 121. The compound of CD Embodiment 34, wherein A¹ is A¹-11, or a pharmaceutically acceptable salt or solvate thereof. CD Embodiment 122.

The compound of CD Embodiment 34, wherein A¹ is A¹-12, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 123. The compound of CD Embodiment 34, wherein A¹ is A¹-13, or a pharmaceutically acceptable salt or solvate thereof.

CD Embodiment 124. The compound of CD Embodiment 1 of Formula XV, see above, or a pharmaceutically acceptable salt or solvate thereof, wherein:

R^1a is selected from the group consisting of hydrogen and C₁-C₃ alkyl;

A¹ is selected from the group consisting of A¹-2, A¹-3, A¹-9, A¹-10, A¹-11, A¹-12, and A¹-13 see above;

Z³ and Z⁴ are independently selected from the group consisting of N and CH;

with the provisos that (i) at least one of Z³ or Z⁴ is CH; and (ii) y¹ and w¹ are 1 when Z⁴ is N;

y, y¹, w, and w¹ are each independently 0 or 1;

m2 is 0 or 1; and

B¹ is selected from the group consisting of B¹-1, B¹-2, B¹-3, B¹-4, B¹-15, B¹-16, B¹-17, B¹-18, B¹-19, B¹-20, B¹-21, B¹-22, B¹-23, B¹-24, B¹-25 and B¹-26, see above.

CD Embodiment 125. The compound of CD Embodiment 124, or a pharmaceutically acceptable salt or solvate thereof, wherein R^1a is methyl.

CD Embodiment 126. The compound of CD Embodiments 124 or 125, or a pharmaceutically acceptable salt or solvate thereof, wherein y is 0 and w is 0.

CD Embodiment 127. The compound of CD Embodiments 124 or 125, or a pharmaceutically acceptable salt or solvate thereof, wherein y is 0 and w is 1.

CD Embodiment 128. The compound of CD Embodiments 124 or 125, or a pharmaceutically acceptable salt or solvate thereof, wherein y is 1 and w is 1.

CD Embodiment 129. The compound of any one of CD Embodiments 124-128, or a pharmaceutically acceptable salt or solvate thereof, wherein Z⁴ is CH, y¹ is 0, and w¹ is 0.

CD Embodiment 130. The compound of any one of CD Embodiments 124-128, or a pharmaceutically acceptable salt or solvate thereof, wherein Z⁴ is CH, y¹ is 0, and w¹ is 1.

CD Embodiment 131. The compound of any one of CD Embodiments 124-128, or a pharmaceutically acceptable salt or solvate thereof, wherein Z⁴ is CH, y¹ is 1, and w¹ is 1.

CD Embodiment 132. The compound of any one of CD Embodiments 124-131, or a pharmaceutically acceptable salt or solvate thereof, wherein m2 is 0.

CD Embodiment 133. The compound of any one of CD Embodiments 124-131, or a pharmaceutically acceptable salt or solvate thereof, wherein m2 is 1.

CD Embodiment 134. The compound of any one of CD Embodiments 124-133, or a pharmaceutically acceptable salt or solvate thereof, wherein A¹ is A¹-1.

CD Embodiment 135. The compound of any one of CD Embodiments 124-133, or a pharmaceutically acceptable salt or solvate thereof, wherein A¹ is A¹-2.

CD Embodiment 136. The compound of any one of CD Embodiments 124-133, or a pharmaceutically acceptable salt or solvate thereof, wherein A¹ is A¹-3.

CD Embodiment 137. The compound of any one of CD Embodiments 124-133, or a pharmaceutically acceptable salt or solvate thereof, wherein A¹ is A¹-9.

CD Embodiment 138. The compound of any one of CD Embodiments 124-133, or a pharmaceutically acceptable salt or solvate thereof, wherein A¹ is A¹-10.

CD Embodiment 139. The compound of any one of CD Embodiments 124-133, or a pharmaceutically acceptable salt or solvate thereof, wherein A¹ is A¹-11.

CD Embodiment 140. The compound of any one of CD Embodiments 124-133, or a pharmaceutically acceptable salt or solvate thereof, wherein A¹ is A¹-12.

CD Embodiment 141. The compound of any one of CD Embodiments 124-133, or a pharmaceutically acceptable salt or solvate thereof, wherein A¹ is A¹-13.

CD Embodiment 142. The compound of any one of CD Embodiments 124-141, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is B¹-1.

CD Embodiment 143. The compound of any one of CD Embodiments 124-141, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is B¹-2.

CD Embodiment 144. The compound of any one of CD Embodiments 124-141, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is B¹-3.

CD Embodiment 145. The compound of any one of CD Embodiments 124-141, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is B¹-4.

CD Embodiment 146. The compound of any one of CD Embodiments 124-141, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is B¹-15.

CD Embodiment 147. The compound of any one of CD Embodiments 124-141, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is B¹-16.

CD Embodiment 148. The compound of any one of CD Embodiments 124-141, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is B¹-17.

CD Embodiment 149. The compound of any one of CD Embodiments 124-141, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is B¹-18.

CD Embodiment 150. The compound of any one of CD Embodiments 124-141, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is B¹-19.

CD Embodiment 151. The compound of any one of CD Embodiments 124-141, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is B¹-20.

CD Embodiment 152. The compound of any one of CD Embodiments 124-141, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is B¹-21.

CD Embodiment 153. The compound of any one of CD Embodiments 124-141, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is B¹-22.

CD Embodiment 154. The compound of any one of CD Embodiments 124-141, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is B¹-23.

CD Embodiment 155. The compound of any one of CD Embodiments 124-141, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is B¹-24.

CD Embodiment 156. The compound of any one of CD Embodiments 124-141, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is B¹-25.

CD Embodiment 157. The compound of any one of CD Embodiments 124-141, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is B¹-26.

CD Embodiment 158. The compound of any one of CD Embodiments 124-141, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is selected from the group consisting of:

CD Embodiment 159. The compound of CD Embodiment 1 of Formula XVI, see above, or a pharmaceutically acceptable salt or solvate thereof, wherein:

R^1a is selected from the group consisting of hydrogen and C₁-C₃ alkyl;

A¹ is selected from the group consisting of A¹-2, A¹-3, A¹-9, A¹-10, A¹-11, A¹-12, and A¹-13, see above;

y² and w² are each independently 0 or 1;

m4 is 0 or 1; and

B¹ is selected from the group consisting of B¹-5, B¹-6, B¹-7, B¹-9, B¹-10, B¹-11, B¹-12, B¹-13, B¹-14, B¹-27, and B¹-28, see above.

CD Embodiment 160. The compound of CD Embodiment 159, or a pharmaceutically acceptable salt or solvate thereof, wherein R^1a is methyl.

CD Embodiment 161. The compound of CD Embodiments 159 or 160, or a pharmaceutically acceptable salt or solvate thereof, wherein y² is 0 and w² is 0.

CD Embodiment 162. The compound of CD Embodiments 159 or 160, or a pharmaceutically acceptable salt or solvate thereof, wherein y² is 0 and w² is 1.

CD Embodiment 163. The compound of CD Embodiments 159 or 160, or a pharmaceutically acceptable salt or solvate thereof, wherein y² is 1 and w² is 1.

CD Embodiment 164. The compound of any one of CD Embodiments 159-163, or a pharmaceutically acceptable salt or solvate thereof, wherein m4 is 0.

CD Embodiment 165. The compound of any one of CD Embodiments 159-163, or a pharmaceutically acceptable salt or solvate thereof, wherein m4 is 1.

CD Embodiment 166. The compound of any one of CD Embodiments 159-165, or a pharmaceutically acceptable salt or solvate thereof, wherein A¹ is A¹-1.

CD Embodiment 167. The compound of any one of CD Embodiments 159-165, or a pharmaceutically acceptable salt or solvate thereof, wherein A¹ is A¹-2.

CD Embodiment 168. The compound of any one of CD Embodiments 159-165, or a pharmaceutically acceptable salt or solvate thereof, wherein A¹ is A¹-3.

CD Embodiment 169. The compound of any one of CD Embodiments 159-165, or a pharmaceutically acceptable salt or solvate thereof, wherein A¹ is A¹-9.

CD Embodiment 170. The compound of any one of CD Embodiments 159-165, or a pharmaceutically acceptable salt or solvate thereof, wherein A¹ is A¹-10.

CD Embodiment 171. The compound of any one of CD Embodiments 159-165, or a pharmaceutically acceptable salt or solvate thereof, wherein A¹ is A¹-11.

CD Embodiment 172. The compound of any one of CD Embodiments 159-165, or a pharmaceutically acceptable salt or solvate thereof, wherein A¹ is A¹-12.

CD Embodiment 173. The compound of any one of CD Embodiments 159-165, or a pharmaceutically acceptable salt or solvate thereof, wherein A¹ is A¹-13.

CD Embodiment 174. The compound of any one of CD Embodiments 159-173, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is B¹-5.

CD Embodiment 175. The compound of any one of CD Embodiments 159-173, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is B¹-6.

CD Embodiment 176. The compound of any one of CD Embodiments 159-173, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is B¹-7.

CD Embodiment 177. The compound of any one of CD Embodiments 159-173, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is B¹-8.

CD Embodiment 178. The compound of any one of CD Embodiments 159-173, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is B¹-9.

CD Embodiment 179. The compound of any one of CD Embodiments 159-173, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is B¹-10.

CD Embodiment 180. The compound of any one of CD Embodiments 159-173, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is B¹-11.

CD Embodiment 181. The compound of any one of CD Embodiments 159-173, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is B¹-12.

CD Embodiment 182. The compound of any one of CD Embodiments 159-173, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is B¹-13.

CD Embodiment 183. The compound of any one of CD Embodiments 159-173, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is B¹-14.

CD Embodiment 184. The compound of any one of CD Embodiments 159-173, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is B¹-27.

CD Embodiment 185. The compound of any one of CD Embodiments 159-173, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is B¹-28.

CD Embodiment 186. The compound of any one of CD Embodiments 159-173, or a pharmaceutically acceptable salt or solvate thereof, wherein B¹ is selected from the group consisting of:

II. Therapeutic Methods of the Disclosure

Compounds of the Disclosure degrade AR protein and are thus useful in the treatment of a variety of diseases and conditions. In particular, Compounds of the Disclosure are useful in methods of treating a disease or condition wherein degradation AR proteins provides a benefit, for example, cancers and proliferative diseases. The therapeutic methods of the disclosure comprise administering a therapeutically effective amount of a Compound of the Disclosure to a subject, e.g., a cancer patient, in need thereof. The present methods also encompass administering a second therapeutic agent to the subject in combination with the Compound of the Disclosure. The second therapeutic agent is selected from drugs known as useful in treating the disease or condition afflicting the individual in need thereof, e.g., a chemotherapeutic agent and/or radiation known as useful in treating a particular cancer.

The present disclosure provides Compounds of the Disclosure as AR protein degraders for the treatment of a variety of diseases and conditions wherein degradation of AR proteins has a beneficial effect. Compounds of the Disclosure typically have DC₅₀ (the drug concentration that results in 50% AR protein degradation) values of less than 100 μM, e.g., less than 50 μM, less than 25 μM, and less than 5 μM, less than about 1 μM, less than about 0.5 μM, or less than about 0.1 μM. In some embodiments, Compounds of the Disclosure typically have DC₅₀ values of less than about 0.01 μM. In some embodiments, Compounds of the Disclosure typically have DC₅₀ values of less than about 0.001 μM. In one embodiment, the present disclosure relates to a method of treating an individual suffering from a disease or condition wherein degradation of AR proteins provides a benefit comprising administering a therapeutically effective amount of a Compound of the Disclosure to an individual in need thereof.

Since Compounds of the Disclosure are degraders of AR protein, a number of diseases and conditions mediated by AR can be treated by employing these compounds. The present disclosure is thus directed generally to a method for treating a condition or disorder responsive to degradation of AR in an animal, e.g., a human, suffering from, or at risk of suffering from, the condition or disorder, the method comprising administering to the animal an effective amount of one or more Compounds of the Disclosure.

The present disclosure is further directed to a method of degrading AR protein in a subject in need thereof, said method comprising administering to the subject an effective amount of at least one Compound of the Disclosure.

In another aspect, the present disclosure provides a method of treating cancer in a subject comprising administering a therapeutically effective amount of a Compound of the Disclosure. While not being limited to a specific mechanism, in some embodiments, Compounds of the Disclosure treat cancer by degrading AR. Examples of treatable cancers include, but are not limited to, any one or more of the cancers of Table 2.

TABLE 2
adrenal cancer	acinic cell carcinoma	acoustic neuroma	acral lentigious
			melanoma
acrospiroma	acute eosinophilic	acute erythroid	acute lymphoblastic
	leukemia	leukemia	leukemia
acute	acute monocytic	acute promyelocytic	adenocarcinoma
megakaryoblastic	leukemia	leukemia
leukemia
adenoid cystic	adenoma	adenomatoid	adenosquamous
carcinoma		odontogenic tumor	carcinoma
adipose tissue	adrenocortical	adult T-cell	aggressive NK-cell
neoplasm	carcinoma	leukemia/lymphoma	leukemia
AIDS-related	alveolar	alveolar soft part	ameloblastic
lymphoma	rhabdomyosarcoma	sarcoma	fibroma
anaplastic large cell	anaplastic thyroid	angioimmunoblastic	angiomyolipoma
lymphoma	cancer	T-cell lymphoma
angiosarcoma	astrocytoma	atypical teratoid	B-cell chronic
		rhabdoid tumor	lymphocytic
			leukemia
B-cell	B-cell lymphoma	basal cell carcinoma	biliary tract cancer
prolymphocytic
leukemia
bladder cancer	blastoma	bone cancer	Brenner tumor
Brown tumor	Burkitt's lymphoma	breast cancer	brain cancer
carcinoma	carcinoma in situ	carcinosarcoma	cartilage tumor
cementoma	myeloid sarcoma	chondroma	chordoma
choriocarcinoma	choroid plexus	clear-cell sarcoma of	craniopharyngioma
	papilloma	the kidney
cutaneous T-cell	cervical cancer	colorectal cancer	Degos disease
lymphoma
desmoplastic small	diffuse large B-cell	dysembryoplastic	dysgerminoma
round cell tumor	lymphoma	neuroepithelial
		tumor
embryonal	endocrine gland	endodermal sinus	enteropathy-
carcinoma	neoplasm	tumor	associated T-cell
			lymphoma
esophageal cancer	fetus in fetu	fibroma	fibrosarcoma
follicular	follicular thyroid	ganglioneuroma	gastrointestinal
lymphoma	cancer		cancer
germ cell tumor	gestational	giant cell	giant cell tumor of
	choriocarcinoma	fibroblastoma	the bone
glial tumor	glioblastoma	glioma	gliomatosis cerebri
	multiforme
glucagonoma	gonadoblastoma	granulosa cell tumor	gynandroblastoma
gallbladder cancer	gastric cancer	hairy cell leukemia	hemangioblastoma
head and neck	hemangiopericytoma	hematological	hepatoblastoma
cancer		cancer
hepatosplenic T-cell	Hodgkin's	non-Hodgkin's	invasive lobular
lymphoma	lymphoma	lymphoma	carcinoma
intestinal cancer	kidney cancer	laryngeal cancer	lentigo maligna
lethal midline	leukemia	leydig cell tumor	liposarcoma
carcinoma
lung cancer	lymphangioma	lymphangiosarcoma	lymphoepithelioma
lymphoma	acute lymphocytic	acute myelogeous	chronic
	leukemia	leukemia	lymphocytic
			leukemia
liver cancer	small cell lung	non-small cell lung	MALT lymphoma
	cancer	cancer
malignant fibrous	malignant peripheral	malignant triton	mantle cell
histiocytoma	nerve sheath tumor	tumor	lymphoma
marginal zone B-	mast cell leukemia	mediastinal germ	medullary
cell lymphoma		cell tumor	carcinoma of the
			breast
medullary thyroid	medulloblastoma	melanoma	meningioma
cancer
merkel cell cancer	mesothelioma	metastatic urothelial	mixed Mullerian
		carcinoma	tumor
mucinous tumor	multiple myeloma	muscle tissue	mycosis fungoides
		neoplasm
myxoid	myxoma	myxosarcoma	nasopharyngeal
liposarcoma			carcinoma
neurinoma	neuroblastoma	neurofibroma	neuroma
nodular melanoma	ocular cancer	oligoastrocytoma	oligodendroglioma
oncocytoma	optic nerve sheath	optic nerve tumor	oral cancer
	meningioma
osteosarcoma	ovarian cancer	Pancoast tumor	papillary thyroid
			cancer
paraganglioma	pinealoblastoma	pineocytoma	pituicytoma
pituitary adenoma	pituitary tumor	plasmacytoma	polyembryoma
precursor T-	primary central	primary effusion	preimary peritoneal
lymphoblastic	nervous system	lymphoma	cancer
lymphoma	lymphoma
prostate cancer	pancreatic cancer	pharyngeal cancer	pseudomyxoma
			periotonei
renal cell carcinoma	renal medullary	retinoblastoma	rhabdomyoma
	carcinoma
rhabdomyosarcoma	Richter's	rectal cancer	sarcoma
	transformation
Schwannomatosis	seminoma	Sertoli cell tumor	sex cord-gonadal
			stromal tumor
signet ring cell	skin cancer	small blue round cell	small cell
carcinoma		tumors	carcinoma
soft tissue sarcoma	somatostatinoma	soot wart	spinal tumor
splenic marginal	squamous cell	synovial sarcoma	Sezary's disease
zone lymphoma	carcinoma
small intestine	squamous carcinoma	stomach cancer	T-cell lymphoma
cancer
testicular cancer	thecoma	thyroid cancer	transitional cell
			carcinoma
throat cancer	urachal cancer	urogenital cancer	urothelial
			carcinoma
uveal melanoma	uterine cancer	verrucous carcinoma	visual pathway
			glioma
vulvar cancer	vaginal cancer	Waldenstrom's	Warthin's tumor
		macroglobulinemia
Wilms' tumor

In another embodiment, the cancer is a solid tumor. In another embodiment, the cancer a hematological cancer. Exemplary hematological cancers include, but are not limited to, the cancers listed in Table 3. In another embodiment, the hematological cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia), or acute myeloid leukemia.

TABLE 3
acute lymphocytic leukemia (ALL) acute eosinophilic leukemia
acute myeloid leukemia (AML)     acute erythroid leukemia
chronic lymphocytic leukemia (CLL) acute lymphoblastic leukemia
small lymphocytic lymphoma (SLL) acute megakaryoblastic leukemia
multiple myeloma (MM)            acute monocytic leukemia
Hodgkins lymphoma (HL)           acute promyelocytic leukemia
non-Hodgkin's lymphoma (NHL)     acute myelogeous leukemia
mantle cell lymphoma (MCL)       B-cell prolymphocytic leukemia
marginal zone B-cell lymphoma    B-cell lymphoma
splenic marginal zone lymphoma   MALT lymphoma
follicular lymphoma (FL)         precursor T-lymphoblastic lymphoma
Waldenstrom's macroglobulinemia (WM) T-cell lymphoma
diffuse large B-cell lymphoma (DLBCL) mast cell leukemia
marginal zone lymphoma (MZL)     adult T cell leukemia/lymphoma
hairy cell leukemia (HCL)        aggressive NK-cell leukemia
Burkitt's lymphoma (BL)          angioimmunoblastic T-cell lymphoma
Richter's transformation

In another embodiment, the cancer is a leukemia, for example a leukemia selected from acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia and mixed lineage leukemia (MLL). In another embodiment the cancer is NUT-midline carcinoma. In another embodiment the cancer is multiple myeloma. In another embodiment the cancer is a lung cancer such as small cell lung cancer (SCLC). In another embodiment the cancer is a neuroblastoma. In another embodiment the cancer is Burkitt's lymphoma. In another embodiment the cancer is cervical cancer. In another embodiment the cancer is esophageal cancer. In another embodiment the cancer is ovarian cancer. In another embodiment the cancer is colorectal cancer. In another embodiment, the cancer is prostate cancer. In another embodiment, the cancer is breast cancer.

In another embodiment, the cancer is selected from the group consisting of acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia mixed lineage leukemia, NUT-midline carcinoma, multiple myeloma, small cell lung cancer, non-small cell lung cancer, neuroblastoma, Burkitt's lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer, breast cancer, bladder cancer, ovary cancer, glioma, sarcoma, esophageal squamous cell carcinoma, and papillary thyroid carcinoma.

In another embodiment, Compounds of the Disclosure are administered to a subject in need thereof to treat breast cancer or prostate cancer. In another embodiment, the cancer is breast cancer. In another embodiment, the cancer is prostate cancer. In another embodiment, the cancer is metastatic castration-resistant prostate cancer.

The methods of the present disclosure can be accomplished by administering a Compound of the Disclosure as the neat compound or as a pharmaceutical composition. Administration of a pharmaceutical composition, or neat Compound of the Disclosure, can be performed during or after the onset of the disease or condition of interest. Typically, the pharmaceutical compositions are sterile, and contain no toxic, carcinogenic, or mutagenic compounds that would cause an adverse reaction when administered.

In one embodiment, a Compound of the Disclosure is administered as a single agent to treat a disease or condition wherein degradation of AR protein provides a benefit. In another embodiment, a Compound of the Disclosure is administered in conjunction with a second therapeutic agent useful in the treatment of a disease or condition wherein degradation of AR protein provides a benefit. The second therapeutic agent is different from the Compound of the Disclosure. A Compound of the Disclosure and the second therapeutic agent can be administered simultaneously or sequentially to achieve the desired effect. In addition, the Compound of the Disclosure and second therapeutic agent can be administered as a single pharmaceutical composition or two separate pharmaceutical compositions.

The second therapeutic agent is administered in an amount to provide its desired therapeutic effect. The effective dosage range for each second therapeutic agent is known in the art, and the second therapeutic agent is administered to an individual in need thereof within such established ranges.

A Compound of the Disclosure and the second therapeutic agent can be administered together as a single-unit dose or separately as multi-unit doses, wherein the Compound of the Disclosure is administered before the second therapeutic agent or vice versa. One or more doses of the Compound of the Disclosure and/or one or more doses of the second therapeutic agent can be administered. The Compound of the Disclosure therefore can be used in conjunction with one or more second therapeutic agents, for example, but not limited to, anticancer agents.

In methods of the present disclosure, a therapeutically effective amount of a Compound of the Disclosure, typically formulated in accordance with pharmaceutical practice, is administered to a subject, e.g., a human cancer patient, in need thereof. Whether such a treatment is indicated depends on the individual case and is subject to medical assessment (diagnosis) that takes into consideration signs, symptoms, and/or malfunctions that are present, the risks of developing particular signs, symptoms and/or malfunctions, and other factors.

A Compound of the Disclosure can be administered by any suitable route, for example by oral, buccal, inhalation, sublingual, rectal, vaginal, intracisternal or intrathecal through lumbar puncture, transurethral, nasal, percutaneous, i.e., transdermal, or parenteral (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, intrapulmonary injection and/or surgical implantation at a particular site) administration. Parenteral administration can be accomplished using a needle and syringe or using a high pressure technique.

Pharmaceutical compositions include those wherein a Compound of the Disclosure is administered in an effective amount to achieve its intended purpose. The exact formulation, route of administration, and dosage is determined by an individual physician in view of the diagnosed condition or disease. Dosage amount and interval can be adjusted individually to provide levels of a Compound of the Disclosure that is sufficient to maintain therapeutic effects.

Toxicity and therapeutic efficacy of the Compounds of the Disclosure can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) of a compound, which defines as the highest dose that causes no toxicity in animals. The dose ratio between the maximum tolerated dose and therapeutic effects (e.g. inhibiting of tumor growth) is the therapeutic index. The dosage can vary within this range depending upon the dosage form employed, and the route of administration utilized. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

A therapeutically effective amount of a Compound of the Disclosure required for use in therapy varies with the nature of the condition being treated, the length of time that activity is desired, and the age and the condition of the patient, and ultimately is determined by the attendant physician. Dosage amounts and intervals can be adjusted individually to provide plasma levels of the AR protein degrader that are sufficient to maintain the desired therapeutic effects. The desired dose conveniently can be administered in a single dose, or as multiple doses administered at appropriate intervals, for example as one, two, three, four or more subdoses per day. Multiple doses often are desired, or required. For example, a Compound of the Disclosure can be administered at a frequency of: four doses delivered as one dose per day at four-day intervals (q4d×4); four doses delivered as one dose per day at three-day intervals (q3d×4); one dose delivered per day at five-day intervals (qd×5); one dose per week for three weeks (qwk3); five daily doses, with two days rest, and another five daily doses (5/2/5); or, any dose regimen determined to be appropriate for the circumstance.

A Compound of the Disclosure used in a method of the present disclosure can be administered in an amount of about 0.005 to about 500 milligrams per dose, about 0.05 to about 250 milligrams per dose, or about 0.5 to about 100 milligrams per dose. For example, a Compound of the Disclosure can be administered, per dose, in an amount of about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 milligrams, including all doses between 0.005 and 500 milligrams.

The dosage of a composition containing a Compound of the Disclosure, or a composition containing the same, can be from about 1 ng/kg to about 200 mg/kg, about 1 μg/kg to about 100 mg/kg, or about 1 mg/kg to about 50 mg/kg. The dosage of a composition can be at any dosage including, but not limited to, about 1 μg/kg. The dosage of a composition may be at any dosage including, but not limited to, about 1 μg/kg, about 10 μg/kg, about 25 μg/kg, about 50 μg/kg, about 75 μg/kg, about 100 μg/kg, about 125 μg/kg, about 150 μg/kg, about 175 μg/kg, about 200 μg/kg, about 225 μg/kg, about 250 μg/kg, about 275 μg/kg, about 300 μg/kg, about 325 μg/kg, about 350 μg/kg, about 375 μg/kg, about 400 μg/kg, about 425 μg/kg, about 450 μg/kg, about 475 μg/kg, about 500 μg/kg, about 525 μg/kg, about 550 μg/kg, about 575 μg/kg, about 600 μg/kg, about 625 μg/kg, about 650 μg/kg, about 675 μg/kg, about 700 μg/kg, about 725 μg/kg, about 750 μg/kg, about 775 μg/kg, about 800 μg/kg, about 825 μg/kg, about 850 μg/kg, about 875 μg/kg, about 900 μg/kg, about 925 μg/kg, about 950 μg/kg, about 975 μg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 60 mg/kg, about 70 mg/kg, about 80 mg/kg, about 90 mg/kg, about 100 mg/kg, about 125 mg/kg, about 150 mg/kg, about 175 mg/kg, about 200 mg/kg, or more. The above dosages are exemplary of the average case, but there can be individual instances in which higher or lower dosages are merited, and such are within the scope of this disclosure. In practice, the physician determines the actual dosing regimen that is most suitable for an individual patient, which can vary with the age, weight, and response of the particular patient.

As stated above, a Compound of the Disclosure can be administered in combination with a second therapeutically active agent. In some embodiments, the second therapeutic agent is an epigenetic drug. As used herein, the term “epigenetic drug” refers to a therapeutic agent that targets an epigenetic regulator. Examples of epigenetic regulators include the histone lysine methyltransferases, histone arginine methyl transferases, histone demethylases, histone deacetylases, histone acetylases, and DNA methyltransferases. Histone deacetylase inhibitors include, but are not limited to, vorinostat.

In another embodiment, chemotherapeutic agents or other anti-proliferative agents can be combined with Compound of the Disclosure to treat proliferative diseases and cancer. Examples of therapies and anticancer agents that can be used in combination with Compounds of the Disclosure include surgery, radiotherapy (e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes), endocrine therapy, a biologic response modifier (e.g., an interferon, an interleukin, tumor necrosis factor (TNF), hyperthermia and cryotherapy, an agent to attenuate any adverse effect (e.g., an antiemetic), and any other approved chemotherapeutic drug.

Examples of antiproliferative compounds include, but are not limited to, an aromatase inhibitor; an anti-estrogen; an anti-androgen; a gonadorelin agonist; a topoisomerase I inhibitor; a topoisomerase II inhibitor; a microtubule active agent; an alkylating agent; a retinoid, a carontenoid, or a tocopherol; a cyclooxygenase inhibitor; an MMP inhibitor; an mTOR inhibitor; an antimetabolite; a platin compound; a methionine aminopeptidase inhibitor; a bisphosphonate; an antiproliferative antibody; a heparanase inhibitor; an inhibitor of Ras oncogenic isoforms; a telomerase inhibitor; a proteasome inhibitor; a compound used in the treatment of hematologic malignancies; a Flt-3 inhibitor; an Hsp90 inhibitor; a kinesin spindle protein inhibitor; a MEK inhibitor; an antitumor antibiotic; a nitrosourea; a compound targeting/decreasing protein or lipid kinase activity, a compound targeting/decreasing protein or lipid phosphatase activity, or any further anti-angiogenic compound.

Nonlimiting exemplary aromatase inhibitors include, but are not limited to, steroids, such as atamestane, exemestane, and formestane, and non-steroids, such as aminoglutethimide, rogletimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole, and letrozole.

Nonlimiting anti-estrogens include, but are not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Anti-androgens include, but are not limited to, bicalutamide. Gonadorelin agonists include, but are not limited to, abarelix, goserelin, and goserelin acetate.

Exemplary topoisomerase I inhibitors include, but are not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogues, 9-nitrocamptothecin, and the macromolecular camptothecin conjugate PNU-166148. Topoisomerase II inhibitors include, but are not limited to, anthracyclines, such as doxorubicin, daunorubicin, epirubicin, idarubicin, and nemorubicin; anthraquinones, such as mitoxantrone and losoxantrone; and podophillotoxines, such as etoposide and teniposide.

Microtubule active agents include microtubule stabilizing, microtubule destabilizing compounds, and microtubulin polymerization inhibitors including, but not limited to, taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine, vinblastine sulfate, vincristine, and vincristine sulfate, and vinorelbine; discodermolides; cochicine and epothilones and derivatives thereof.

Exemplary nonlimiting alkylating agents include cyclophosphamide, ifosfamide, melphalan, and nitrosoureas, such as carmustine and lomustine.

Exemplary nonlimiting cyclooxygenase inhibitors include Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib, rofecoxib, etoricoxib, valdecoxib, or a 5-alkyl-2-arylaminophenylacetic acid, such as lumiracoxib.

Exemplary nonlimiting matrix metalloproteinase inhibitors (“MMP inhibitors”) include collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, batimastat, marimastat, prinomastat, metastat, BMS-279251, BAY 12-9566, TAA211, MMI270B, and AAJ996.

Exemplary nonlimiting mTOR inhibitors include compounds that inhibit the mammalian target of rapamycin (mTOR) and possess antiproliferative activity such as sirolimus, everolimus, CCI-779, and ABT578.

Exemplary nonlimiting antimetabolites include 5-fluorouracil (5-FU), capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists, such as pemetrexed.

Exemplary nonlimiting platin compounds include carboplatin, cis-platin, cisplatinum, and oxaliplatin.

Exemplary nonlimiting methionine aminopeptidase inhibitors include bengamide or a derivative thereof and PPI-2458.

Exemplary nonlimiting bisphosphonates include etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid.

Exemplary nonlimiting antiproliferative antibodies include trastuzumab, trastuzumab-DM1, cetuximab, bevacizumab, rituximab, PR064553, and 2C4. The term “antibody” is meant to include intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.

Exemplary nonlimiting heparanase inhibitors include compounds that target, decrease, or inhibit heparin sulfate degradation, such as PI-88 and OGT2115.

The term “an inhibitor of Ras oncogenic isoforms,” such as H-Ras, K-Ras, or N-Ras, as used herein refers to a compound which targets, decreases, or inhibits the oncogenic activity of Ras, for example, a farnesyl transferase inhibitor, such as L-744832, DK8G557, tipifarnib, and lonafarnib.

Exemplary nonlimiting telomerase inhibitors include compounds that target, decrease, or inhibit the activity of telomerase, such as compounds that inhibit the telomerase receptor, such as telomestatin.

Exemplary nonlimiting proteasome inhibitors include compounds that target, decrease, or inhibit the activity of the proteasome including, but not limited to, bortezomid.

The phrase “compounds used in the treatment of hematologic malignancies” as used herein includes FMS-like tyrosine kinase inhibitors, which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, I-β-D-arabinofuransylcytosine (ara-c), and bisulfan; and ALK inhibitors, which are compounds which target, decrease, or inhibit anaplastic lymphoma kinase.

Exemplary nonlimiting Flt-3 inhibitors include PKC412, midostaurin, a staurosporine derivative, SU11248, and MLN518.

Exemplary nonlimiting HSP90 inhibitors include compounds targeting, decreasing, or inhibiting the intrinsic ATPase activity of HSP90; or degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway. Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HDAC inhibitors.

The phrase “a compound targeting/decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or any further anti-angiogenic compound” as used herein includes a protein tyrosine kinase and/or serine and/or threonine kinase inhibitor or lipid kinase inhibitor, such as a) a compound targeting, decreasing, or inhibiting the activity of the platelet-derived growth factor-receptors (PDGFR), such as a compound that targets, decreases, or inhibits the activity of PDGFR, such as an N-phenyl-2-pyrimidine-amine derivatives, such as imatinib, SUlOl, SU6668, and GFB-111; b) a compound targeting, decreasing, or inhibiting the activity of the fibroblast growth factor-receptors (FGFR); c) a compound targeting, decreasing, or inhibiting the activity of the insulin-like growth factor receptor I (IGF-IR), such as a compound that targets, decreases, or inhibits the activity of IGF-IR; d) a compound targeting, decreasing, or inhibiting the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) a compound targeting, decreasing, or inhibiting the activity of the Ax1 receptor tyrosine kinase family; f) a compound targeting, decreasing, or inhibiting the activity of the Ret receptor tyrosine kinase; g) a compound targeting, decreasing, or inhibiting the activity of the Kit/SCFR receptor tyrosine kinase, such as imatinib; h) a compound targeting, decreasing, or inhibiting the activity of the c-Kit receptor tyrosine kinases, such as imatinib; i) a compound targeting, decreasing, or inhibiting the activity of members of the c-Abl family, their gene-fusion products (e.g. Bcr-Abl kinase) and mutants, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib; PD180970; AG957; NSC 680410; PD173955; or dasatinib; j) a compound targeting, decreasing, or inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine/threonine kinases, members of the MEK, SRC, JAK, FAK, PDK1, PKB/Akt, and Ras/MAPK family members, and/or members of the cyclin-dependent kinase family (CDK), such as a staurosporine derivative disclosed in U.S. Pat. No. 5,093,330, such as midostaurin; examples of further compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine; ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196; a isochinoline compound; a farnesyl transferase inhibitor; PD184352 or QAN697, or AT7519; k) a compound targeting, decreasing or inhibiting the activity of a protein-tyrosine kinase, such as imatinib mesylate or a tyrphostin, such as Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin); 1) a compound targeting, decreasing, or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as CP 358774, ZD 1839, ZM 105180; trastuzumab, cetuximab, gefitinib, erlotinib, OSI-774, Cl-1033, EKB-569, GW-2016, antibodies E.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 and E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; and m) a compound targeting, decreasing, or inhibiting the activity of the c-Met receptor.

Exemplary compounds that target, decrease, or inhibit the activity of a protein or lipid phosphatase include inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.

Further anti-angiogenic compounds include compounds having another mechanism for their activity unrelated to protein or lipid kinase inhibition, e.g., thalidomide and TNP-470.

Additional, nonlimiting, exemplary chemotherapeutic compounds, one or more of which may be used in combination with a Compound of the Disclosure, include: daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum, PKC412, 6-mercaptopurine (6-MP), fludarabine phosphate, octreotide, SOM230, FTY720, 6-thioguanine, cladribine, 6-mercaptopurine, pentostatin, hydroxyurea, 2-hydroxy-1H-isoindole-1,3-dione derivatives, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate, angiostatin, endostatin, anthranilic acid amides, ZD4190, ZD6474, SU5416, SU6668, bevacizumab, rhuMAb, rhuFab, macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody, RPI 4610, bevacizumab, porfimer sodium, anecortave, triamcinolone, hydrocortisone, 11-a-epihydrocotisol, cortex olone, 17a-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, dexamethasone, fluocinolone, a plant alkaloid, a hormonal compound and/or antagonist, a biological response modifier, such as a lymphokine or interferon, an antisense oligonucleotide or oligonucleotide derivative, shRNA, and siRNA.

Other examples of second therapeutic agents, one or more of which a Compound of the Disclosure also can be combined, include, but are not limited to: a treatment for Alzheimer's Disease, such as donepezil and rivastigmine; a treatment for Parkinson's Disease, such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; an agent for treating multiple sclerosis (MS) such as beta interferon (e.g., AVONEX® and REBIF®), glatiramer acetate, and mitoxantrone; a treatment for asthma, such as albuterol and montelukast; an agent for treating schizophrenia, such as zyprexa, risperdal, seroquel, and haloperidol; an anti-inflammatory agent, such as a corticosteroid, a TNF blocker, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; an immunomodulatory agent, including immunosuppressive agents, such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, an interferon, a corticosteroid, cyclophosphamide, azathioprine, and sulfasalazine; a neurotrophic factor, such as an acetylcholinesterase inhibitor, an MAO inhibitor, an interferon, an anti-convulsant, an ion channel blocker, riluzole, or an anti-Parkinson's agent; an agent for treating cardiovascular disease, such as a beta-blocker, an ACE inhibitor, a diuretic, a nitrate, a calcium channel blocker, or a statin; an agent for treating liver disease, such as a corticosteroid, cholestyramine, an interferon, and an anti-viral agent; an agent for treating blood disorders, such as a corticosteroid, an anti-leukemic agent, or a growth factor; or an agent for treating immunodeficiency disorders, such as gamma globulin.

In another embodiment, the second therapeutically active agent is an immune checkpoint inhibitor. Examples of immune checkpoint inhibitors include PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, LAG3 inhibitors, TIM3 inhibitors, cd47 inhibitors, and B7-H1 inhibitors. Thus, in one embodiment, a Compound of the Disclosure is administered in combination with an immune checkpoint inhibitor is selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, a LAG3 inhibitor, a TIM3 inhibitor, and a cd47 inhibitor.

In another embodiment, the immune checkpoint inhibitor is a programmed cell death (PD-1) inhibitor. PD-1 is a T-cell coinhibitory receptor that plays a pivotal role in the ability of tumor cells to evade the host's immune system. Blockage of interactions between PD-1 and PD-L1, a ligand of PD-1, enhances immune function and mediates antitumor activity. Examples of PD-1 inhibitors include antibodies that specifically bind to PD-1. Particular anti-PD-1 antibodies include, but are not limited to nivolumab, pembrolizumab, STI-A1014, and pidilzumab. For a general discussion of the availability, methods of production, mechanism of action, and clinical studies of anti-PD-1 antibodies, see U.S. 2013/0309250, U.S. Pat. Nos. 6,808,710, 7,595,048, 8,008,449, 8,728,474, 8,779,105, 8,952,136, 8,900,587, 9,073,994, 9,084,776, and Naido et al., British Journal of Cancer 111:2214-19 (2014).

In another embodiment, the immune checkpoint inhibitor is a PD-L1 (also known as B7-H1 or CD274) inhibitor. Examples of PD-L1 inhibitors include antibodies that specifically bind to PD-L1. Particular anti-PD-L1 antibodies include, but are not limited to, avelumab, atezolizumab, durvalumab, and BMS-936559. For a general discussion of the availability, methods of production, mechanism of action, and clinical studies, see U.S. Pat. No. 8,217,149, U.S. 2014/0341917, U.S. 2013/0071403, WO 2015036499, and Naido et al., British Journal of Cancer 111:2214-19 (2014).

In another embodiment, the immune checkpoint inhibitor is a CTLA-4 inhibitor. CTLA-4, also known as cytotoxic T-lymphocyte antigen 4, is a protein receptor that downregulates the immune system. CTLA-4 is characterized as a “brake” that binds costimulatory molecules on antigen-presenting cells, which prevents interaction with CD28 on T cells and also generates an overtly inhibitory signal that constrains T cell activation. Examples of CTLA-4 inhibitors include antibodies that specifically bind to CTLA-4. Particular anti-CTLA-4 antibodies include, but are not limited to, ipilimumab and tremelimumab. For a general discussion of the availability, methods of production, mechanism of action, and clinical studies, see U.S. Pat. Nos. 6,984,720, 6,207,156, and Naido et al., British Journal of Cancer 111:2214-19 (2014).

In another embodiment, the immune checkpoint inhibitor is a LAG3 inhibitor. LAG3, Lymphocyte Activation Gene 3, is a negative co-stimulatory receptor that modulates T cell homeostatis, proliferation, and activation. In addition, LAG3 has been reported to participate in regulatory T cells (Tregs) suppressive function. A large proportion of LAG3 molecules are retained in the cell close to the microtubule-organizing center, and only induced following antigen specific T cell activation. U.S. 2014/0286935. Examples of LAG3 inhibitors include antibodies that specifically bind to LAG3. Particular anti-LAG3 antibodies include, but are not limited to, GSK2831781. For a general discussion of the availability, methods of production, mechanism of action, and studies, see, U.S. 2011/0150892, U.S. 2014/0093511, U.S. 20150259420, and Huang et al., Immunity 21:503-13 (2004).

In another embodiment, the immune checkpoint inhibitor is a TIM3 inhibitor. TIM3, T-cell immunoglobulin and mucin domain 3, is an immune checkpoint receptor that functions to limit the duration and magnitude of T_H1 and T_C1 T-cell responses. The TIM3 pathway is considered a target for anticancer immunotherapy due to its expression on dysfunctional CD8⁺ T cells and Tregs, which are two reported immune cell populations that constitute immunosuppression in tumor tissue. Anderson, Cancer Immunology Research 2:393-98 (2014). Examples of TIM3 inhibitors include antibodies that specifically bind to TIM3. For a general discussion of the availability, methods of production, mechanism of action, and studies of TIM3 inhibitors, see U.S. 20150225457, U.S. 20130022623, U.S. Pat. No. 8,522,156, Ngiow et al., Cancer Res 71: 6567-71 (2011), Ngiow, et al., Cancer Res 71:3540-51 (2011), and Anderson, Cancer Immunology Res 2:393-98 (2014).

In another embodiment, the immune checkpoint inhibitor is a cd47 inhibitor. See Unanue, E. R., PNAS 110:10886-87 (2013).

The term “antibody” is meant to include intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity. In another embodiment, “antibody” is meant to include soluble receptors that do not possess the Fc portion of the antibody. In one embodiment, the antibodies are humanized monoclonal antibodies and fragments thereof made by means of recombinant genetic engineering.

Another class of immune checkpoint inhibitors include polypeptides that bind to and block PD-1 receptors on T-cells without triggering inhibitor signal transduction. Such peptides include B7-DC polypeptides, B7-H1 polypeptides, B7-1 polypeptides and B7-2 polypeptides, and soluble fragments thereof, as disclosed in U.S. Pat. No. 8,114,845.

Another class of immune checkpoint inhibitors include compounds with peptide moieties that inhibit PD-1 signaling. Examples of such compounds are disclosed in U.S. Pat. No. 8,907,053.

Another class of immune checkpoint inhibitors include inhibitors of certain metabolic enzymes, such as indoleamine 2,3 dioxygenase (IDO), which is expressed by infiltrating myeloid cells and tumor cells. The IDO enzyme inhibits immune responses by depleting amino acids that are necessary for anabolic functions in T cells or through the synthesis of particular natural ligands for cytosolic receptors that are able to alter lymphocyte functions. Pardoll, Nature Reviews. Cancer 12:252-64 (2012); Löb, Cancer Immunol Immunother 58:153-57 (2009). Particular IDO blocking agents include, but are not limited to levo-1-methyl typtophan (L-1MT) and 1-methyl-tryptophan (1MT). Qian et al., Cancer Res 69:5498-504 (2009); and Löb et al., Cancer Immunol Immunother 58:153-7 (2009).

In one embodiment, the immune checkpoint inhibitor is nivolumab, pembrolizumab, pidilizumab, STI-A1110, avelumab, atezolizumab, durvalumab, STI-A1014, ipilimumab, tremelimumab, GSK2831781, BMS-936559 or MED14736

The above-mentioned second therapeutically active agents, one or more of which can be used in combination with a Compound of the Disclosure, are prepared and administered as described in the art.

Compounds of the Disclosure typically are administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions for use in accordance with the present disclosure are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of Compound of the Disclosure.

These pharmaceutical compositions can be manufactured, for example, by conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping, or lyophilizing processes. Proper formulation is dependent upon the route of administration chosen. When a therapeutically effective amount of the Compound of the Disclosure is administered orally, the composition typically is in the form of a tablet, capsule, powder, solution, or elixir. When administered in tablet form, the composition additionally can contain a solid carrier, such as a gelatin or an adjuvant. The tablet, capsule, and powder contain about 0.01% to about 95%, and preferably from about 1% to about 50%, of a Compound of the Disclosure. When administered in liquid form, a liquid carrier, such as water, petroleum, or oils of animal or plant origin, can be added. The liquid form of the composition can further contain physiological saline solution, dextrose or other saccharide solutions, or glycols. When administered in liquid form, the composition contains about 0.1% to about 90%, and preferably about 1% to about 50%, by weight, of a Compound of the Disclosure.

When a therapeutically effective amount of a Compound of the Disclosure is administered by intravenous, cutaneous, or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable solutions, having due regard to pH, isotonicity, stability, and the like, is within the skill in the art. A preferred composition for intravenous, cutaneous, or subcutaneous injection typically contains, an isotonic vehicle.

Compounds of the Disclosure can be readily combined with pharmaceutically acceptable carriers well-known in the art. Standard pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 19th ed. 1995. Such carriers enable the active agents to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by adding the Compound of the Disclosure to a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.

Suitable excipients include fillers such as saccharides (for example, lactose, sucrose, mannitol or sorbitol), cellulose preparations, calcium phosphates (for example, tricalcium phosphate or calcium hydrogen phosphate), as well as binders such as starch paste (using, for example, maize starch, wheat starch, rice starch, or potato starch), gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, one or more disintegrating agents can be added, such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Buffers and pH modifiers can also be added to stabilize the pharmaceutical composition.

Auxiliaries are typically flow-regulating agents and lubricants such as, for example, silica, talc, stearic acid or salts thereof (e.g., magnesium stearate or calcium stearate), and polyethylene glycol. Dragee cores are provided with suitable coatings that are resistant to gastric juices. For this purpose, concentrated saccharide solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate can be used. Dye stuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.

Compound of the Disclosure can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampules or in multidose containers, with an added preservative. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and/or dispersing agents.

Pharmaceutical compositions for parenteral administration include aqueous solutions of the active agent in water-soluble form. Additionally, suspensions of a Compound of the Disclosure can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension. Optionally, the suspension also can contain suitable stabilizers or agents that increase the solubility of the compounds and allow for the preparation of highly concentrated solutions. Alternatively, a present composition can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

Compounds of the Disclosure also can be formulated in rectal compositions, such as suppositories or retention enemas, e.g., containing conventional suppository bases. In addition to the formulations described previously, the Compound of the Disclosure also can be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the Compound of the Disclosure can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins.

In particular, the Compounds of the Disclosure can be administered orally, buccally, or sublingually in the form of tablets containing excipients, such as starch or lactose, or in capsules or ovules, either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. Such liquid preparations can be prepared with pharmaceutically acceptable additives, such as suspending agents. Compound of the Disclosure also can be injected parenterally, for example, intravenously, intramuscularly, subcutaneously, or intracoronarily. For parenteral administration, the Compound of the Disclosure are typically used in the form of a sterile aqueous solution which can contain other substances, for example, salts or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood.

The disclosure provides the following particular embodiments in connection with treating a disease in a subject.

Embodiment I. A method of treating a subject, the method comprising administering to the subject a therapeutically effective amount of a Compound of the Disclosure, e.g., a compound of any one of CD Embodiments 1-117, wherein the subject has cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.

Embodiment II. The method Embodiment I, wherein the subject has cancer, e.g., any one of more of the cancers of Table 2 or Table 3.

Embodiment III. The method of Embodiment II, wherein the cancer is prostate cancer or breast cancer.

Embodiment IV. The method of Embodiment II, wherein the cancer is breast cancer.

Embodiment V. The method of Embodiment II, wherein the cancer is prostate cancer, e.g., metastatic castration-resistant prostate cancer.

Embodiment VI. The method of any one of Embodiments I-V further comprising administering a therapeutically effective amount of a second therapeutic agent useful in the treatment of the disease or condition, e.g., an immune checkpoint inhibitor or other anticancer agent.

Embodiment VII. A pharmaceutical composition comprising a Compound of the Disclosure, e.g., a compound of any one of CD Embodiments 1-117, and a pharmaceutically acceptable excipient for use in treating cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.

Embodiment VIII. The pharmaceutical composition of Embodiment VII for use in treating cancer.

Embodiment IX. The pharmaceutical composition of Embodiment VIII, wherein the cancer is prostate cancer or breast cancer.

Embodiment X. The pharmaceutical composition of Embodiment VIII, wherein the cancer is breast cancer.

Embodiment XI. The pharmaceutical composition of Embodiment VIII, wherein the cancer is prostate cancer, e.g., metastatic castration-resistant prostate cancer.

Embodiment XII. A Compound of the Disclosure, e.g., a compound of any one of CD Embodiments 1-117, for use in treatment of cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.

Embodiment XIII. The compound of Embodiment XIII for use in treating cancer.

Embodiment XIV. The compound of Embodiment XIII, wherein the cancer is breast cancer.

Embodiment XV. The compound of Embodiment XIII, wherein the cancer is prostate cancer, e.g., metastatic castration-resistant prostate cancer.

Embodiment XVI. Use of a Compound of the Disclosure, e.g., a compound of any one of CD Embodiments 1-117, for the manufacture of a medicament for treatment of cancer, a chronic autoimmune disorder, an inflammatory condition, a proliferative disorder, sepsis, or a viral infection.

Embodiment XVII. The use of Embodiment XVI for the treatment of cancer.

Embodiment XVIII. The use of Embodiment XVII, wherein the cancer is prostate cancer or breast cancer.

Embodiment XIV. The use of Embodiment XVII, wherein the cancer is breast cancer.

Embodiment XX. The use of Embodiment XVII, wherein the cancer is prostate cancer, e.g., metastatic castration-resistant prostate cancer.

Embodiment XXI. A method of reducing AR protein within a cell of a subject in need thereof, the method comprising administering to the patient a Compound of the Disclosure, e.g., a compound of any one of CD Embodiments 1-117. In one embodiment, the AR protein is reduced by about 50% or less, e.g., 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or about 45%. In one embodiment, the AR protein is reduced by about 51% or more, e.g., about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%.

III. Intermediates of the Disclosure

In another aspect, the present disclosure provides Intermediates of the Disclosure. Intermediates of the Disclosure are compounds that can be used to prepare the heterobifunctional Compounds of the Disclosure.

In another aspect, the present disclosure provides the following particular embodiments drawn to Intermediates of the Disclosure referred to as “ID Embodiment 1,” “ID Embodiment 2,” “ID Embodiment 3,” and so on.

ID Embodiment 1. A compound of Formula II:

wherein:

R^3a is selected from the group consisting of halo, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;

Z¹ is selected from the group consisting of ═C(H)— and ═N—;

Z² is selected from the group consisting of ═C(R^3b)— and ═N—;

R^3b is selected from the group consisting of hydrogen, halo, C₁-C₄ alkyl, and C₁-C₄ haloalkyl;

E is a spiroheterocyclenyl;

X¹ is selected from the group consisting of —C(═O)—, —S(═O)₂—, and —CR^4aR^4b—; or

X¹ is absent;

R^4a and R^4b are independently selected from the group consisting of hydrogen and C₁-C₃ alkyl;

A¹ is selected from the group consisting of cycloalkylenyl, heterocyclenyl, phenylenyl, and heteroarylenyl;

X² is selected from the group consisting of —C(═O)—, —S(═O)₂—, —O—, and —CR^4cR^4d—; or

X² is absent;

R^4c and R^4d are independently selected from the group consisting of hydrogen and C_1-3 alkyl;

L is -J¹-J²-J³-J⁴-J⁵-,

wherein J₁ is attached to X²;

J¹ is selected from the group consisting of cycloalkylenyl and heterocyclenyl; or

J¹ is absent;

J² is selected from the group consisting of —(CH₂)_m1—, —CH═CH—, and —C≡C—;

m1 is 0, 1, 2, or 3;

J³ is selected from the group consisting of alkylenyl, heteroalkylenyl, cycloalkylenyl, heterocyclenyl, phenylenyl, and heteroarylenyl; or

J³ is absent;

J⁴ is selected from the group consisting of alkylenyl, cycloalkylenyl, and heterocyclenyl; or

J⁴ is absent;

J⁵ is selected from the group consisting of —(CH2)_m2—, —O—, —N(R⁶)—, and —C(═O)—;

m2 is 0, 1, 2, or 3;

R⁶ is selected from the group consisting of hydrogen and C₁-C₃ alkyl;

B² is selected from the group consisting of hydrogen, —CHO, and B²-1:

m3 is 0, 1, or 2;

n3 is 0, 1, or 2;

each R^1h is independently C₁-C₃ alkyl; and

k1 is 0, 1, or 2, or a salt or solvate thereof.

ID Embodiment 2. The compound of ID Embodiment 1, wherein E is selected from the group consisting of E-1, E-2, and E-3, see above;

wherein the bond designated with an “*” is attached to X¹;

o and p are independently 0 or 1;

q and r are independently 0, 1, 2, or 3;

wherein the sum of o, p, q, and r is 2, 3, 4, 5, 6, or 7;

s is 0, 1, 2, 3, or 4;

t, u, v, w, and x are independently 0, 1, 2, or 3;

R^1a and R^1b are independently selected from the group consisting of hydrogen, C₁-C₃ alkyl, C₁-C₄ haloalkyl, optionally substituted C₃-C₆ cycloalkyl, and (C₃-C₆ cycloalkyl)C₁-C₆ alkyl; or

R^1a and R^1b taken together with the carbon atom to which they are attached form an —C(═O)— group; or

R^1a and R^1b taken together with the carbon atom to which they are attached form an optionally substituted C₃-C₆ cycloalkyl; or

R^1a and R^1b taken together with the carbon atom to which they are attached form an optionally substituted 4- to 6-membered heterocyclo;

R^1c and R^1d are independently selected from the group consisting of hydrogen and C₁-C₃ alkyl; or

R^1c and R^1d taken together with the carbon atom to which they are attached form an —C(═O)— group;

each R^1e is independently C₁-C₃ alkyl;

j is 0, 1, 2, 3, or 4;

each R^1f is independently C₁-C₃ alkyl;

k is 0, 1, 2, 3, or 4;

each R^1g is independently C₁-C₃ alkyl; and

h is 0, 1, 2, 3, or 4, or a salt or solvate thereof.

ID Embodiment 3. The compound of ID Embodiment 2, wherein E is E-1, or a salt or solvate thereof.

ID Embodiment 4. The compound of ID Embodiment 3, wherein E-1 is selected from the group consisting of E-1-1 and E-1-2, see above, or a salt or solvate thereof.

ID Embodiment 5. The compound of ID Embodiment 4, wherein E-1 is E-1-1, or a salt or solvate thereof.

ID Embodiment 6. The compound of ID Embodiment 5, wherein R^1a and R^1b are hydrogen, or a salt or solvate thereof.

ID Embodiment 7. The compound of ID Embodiment 6, wherein q, r, s, and t are 1, or a salt or solvate thereof.

ID Embodiment 8. The compound of ID Embodiment 6, wherein q is 2; r is 1; s is 0; and t is 1, or a salt or solvate thereof.

ID Embodiment 9. The compound of ID Embodiment 6, wherein q is 1; r is 0; s is 0; and t is 2, or a salt or solvate thereof.

ID Embodiment 10. The compound of ID Embodiment 6, wherein q is 0; r is 1; s is 1; and t is 1, or a salt or solvate thereof.

ID Embodiment 11. The compound of ID Embodiment 6, wherein q is 1; r is 1; s is 0; and t is 1, or a salt or solvate thereof

ID Embodiment 12. The compound of ID Embodiment 5, wherein R^1a and R^1b are independently C₁-C₃ alkyl, or a salt or solvate thereof.

ID Embodiment 13. The compound of ID Embodiment 12, wherein q, r, s, and t are 1, or a salt or solvate thereof.

ID Embodiment 14. The compound of ID Embodiment 5, wherein R^1a is C₁-C₃ alkyl; and R^1b is hydrogen or a salt or solvate thereof.

ID Embodiment 15. The compound of ID Embodiment 14, wherein q, r, s, and t are 1, or a salt or solvate thereof.

ID Embodiment 16. The compound of ID Embodiment 15 of Formula IX:

or a salt or solvate thereof.

ID Embodiment 17. The compound of ID Embodiment 15 of Formula X:

or a salt or solvate thereof.

ID Embodiment 18. The compound of ID Embodiment 5, wherein R^1a and R^1b taken together with the carbon atom to which they are attached form an —C(═O)— group, or a salt or solvate thereof.

ID Embodiment 19. The compound of ID Embodiment 18, wherein q, r, s, and t are 1, or a salt or solvate thereof.

ID Embodiment 20. The compound of ID Embodiment 4, wherein:

E-1 is E-1-2;

R^1c is C₁-C₃ alkyl;

R^1d is selected from the group consisting of hydrogen and C₁-C₃ alkyl; or

R^1c and R^1d taken together with the carbon atom to which they are attached form an —C(═O)— group, or a salt or solvate thereof.

ID Embodiment 21. The compound of ID Embodiment 20, wherein R^1d is hydrogen, or a salt or solvate thereof.

ID Embodiment 22. The compound of ID Embodiment 21 of Formula XI:

or a salt or solvate thereof.

ID Embodiment 23. The compound of ID Embodiment 21 of Formula XII:

or a salt or solvate thereof.

ID Embodiment 24. The compound of ID Embodiment 20, wherein R^1c and R^1d taken together with the carbon atom to which they are attached form an —C(═O)— group, or a salt or solvate thereof.

ID Embodiment 25. The compound of ID Embodiment 2, wherein E is E-2, or a salt or solvate thereof.

ID Embodiment 26. The compound of ID Embodiment 25, wherein E-2 is E-2-1, see above, or a salt or solvate thereof.

ID Embodiment 27. The compound of ID Embodiment 2, wherein E is E-3, or a salt or solvate thereof.

ID Embodiment 28. The compound of ID Embodiment 27, wherein E-3 is E-3-1, see above, or a salt or solvate thereof.

ID Embodiment 29. The compound of any one of ID Embodiments 1-26, wherein X¹ is —C(═O)—, or a salt or solvate thereof.

ID Embodiment 30. The compound of any one of ID Embodiments 1-26, wherein X¹ is —S(═O)₂—, or a salt or solvate thereof.

ID Embodiment 31. The compound of any one of ID Embodiments 1-26, wherein X¹ is —CR^4aR^4b—, or a salt or solvate thereof.

ID Embodiment 32. The compound of ID Embodiments 31, wherein R^4a and R^4b are hydrogen, or a salt or solvate thereof.

ID Embodiment 33. The compound of any one of ID Embodiments 1-28, wherein X¹ is absent, or a salt or solvate thereof.

ID Embodiment 34. The compound of any one of ID Embodiments 1-33, wherein:

A¹ is selected from the group consisting of A¹-1, A¹-2, A¹-3, A¹-4, A¹-5, A¹-6, A¹-7, and A¹-8, see above, wherein the bond designated with an “*” is attached to X²;

R^5a, R^5b, R^5c and R^5d are each independently selected from the group consisting of hydrogen, halo, C₁-C₃ alkyl, and C₁-C₃ alkoxy

e is 0, 1, or 2; and

f is 0, 1, or 2, or a salt or solvate thereof.

ID Embodiment 35. The compound of ID Embodiment 34, wherein A¹ is A¹-1, or a salt or solvate thereof.

ID Embodiment 36. The compound of ID Embodiment 34, wherein A¹ is A¹-2, or a salt or solvate thereof.

ID Embodiment 37. The compound of ID Embodiment 34, wherein A¹ is A¹-3, or a salt or solvate thereof.

ID Embodiment 38. The compound of ID Embodiment 34, wherein A¹ is A¹-4, or a salt or solvate thereof.

ID Embodiment 39. The compound of ID Embodiment 34, wherein A¹ is A¹-5, or a salt or solvate thereof.

ID Embodiment 40. The compound of ID Embodiment 34, wherein A¹ is A¹-6, or a salt or solvate thereof.

ID Embodiment 41. The compound of ID Embodiment 34, wherein A¹ is A¹-7, or a salt or solvate thereof.

ID Embodiment 42. The compound of any one of ID Embodiments 34-41, wherein R^5a, R^5b, R^5c, and R^5d are hydrogen, or a salt or solvate thereof.

ID Embodiment 43. The compound of any one of ID Embodiments 1-42, wherein X² is —C(═O)—, or a salt or solvate thereof.

ID Embodiment 44. The compound of any one of ID Embodiments 1-42, wherein X² is —S(═O)₂—, or a salt or solvate thereof.

ID Embodiment 45. The compound of any one of ID Embodiments 1-42, wherein X² is —O—, or a salt or solvate thereof.

ID Embodiment 46. The compound of any one of ID Embodiments 1-42, wherein X² is —CR^4cR^4d—, or a salt or solvate thereof.

ID Embodiment 47. The compound of ID Embodiment 46, wherein R^4c and R^4d are hydrogen, or a salt or solvate thereof.

ID Embodiment 48. The compound of any one of ID Embodiments 1-42, wherein X² is absent, or a salt or solvate thereof.

ID Embodiment 49. The compound of any one of ID Embodiments 1-48, wherein J¹ is cycloalkylenyl, or a salt or solvate thereof.

ID Embodiment 50. The compound of any one of ID Embodiments 1-48, wherein J¹ is heterocyclenyl, or a salt or solvate thereof.

ID Embodiment 51. The compound of ID Embodiment 20, wherein J¹ is selected from the group consisting of J¹-1, J¹-2, J¹-3, J¹-4, J¹-5, J¹-6, J¹-7, J¹-8, J¹-9, J¹-10, J¹-11, J¹-12, and J¹-13, see above, or a salt or solvate thereof.

ID Embodiment 52. The compound of ID Embodiment 51, wherein J¹ is J¹-1, or a salt or solvate thereof.

ID Embodiment 53. The compound of ID Embodiment 51, wherein J¹ is J¹-2, or a salt or solvate thereof.

ID Embodiment 54. The compound of ID Embodiment 51, wherein J¹ is J¹-3, or a salt or solvate thereof.

ID Embodiment 55. The compound of ID Embodiment 51, wherein J¹ is J¹-4, or a salt or solvate thereof.

ID Embodiment 56. The compound of ID Embodiment 51, wherein J¹ is J¹-5, or a salt or solvate thereof.

ID Embodiment 57. The compound of ID Embodiment 51, wherein J¹ is J¹-6, or a salt or solvate thereof.

ID Embodiment 58. The compound of ID Embodiment 51, wherein J¹ is J¹-7, or a salt or solvate thereof.

ID Embodiment 59. The compound of ID Embodiment 51, wherein J¹ is J¹-8, or a salt or solvate thereof.

ID Embodiment 60. The compound of ID Embodiment 51, wherein J¹ is J¹-9, or a salt or solvate thereof.

ID Embodiment 61. The compound of ID Embodiment 51, wherein J¹ is J¹-10, or a salt or solvate thereof.

ID Embodiment 62. The compound of ID Embodiment 51, wherein J¹ is J¹-11, or a salt or solvate thereof.

ID Embodiment 63. The compound of ID Embodiment 51, wherein J¹ is J¹-12, or a salt or solvate thereof.

ID Embodiment 64. The compound of ID Embodiment 51, wherein J¹ is J¹-13, or a salt or solvate thereof.

ID Embodiment 65. The compound of any one of ID Embodiments, 1-48, wherein J¹ is absent, or a salt or solvate thereof.

ID Embodiment 66. The compound of any one of ID Embodiments 1-65, wherein J² is selected from the group consisting of —(CH₂)_m1— and —C≡C—; and m1 is 0, 1, or 2, or a salt or solvate thereof.

ID Embodiment 67. The compound of ID Embodiment 66, wherein J² is —(CH₂)_m1—; and m1 is 0, or a salt or solvate thereof.

ID Embodiment 68. The compound of ID Embodiment 66, wherein J² is —(CH₂)_m1—; and m1 is 1, or a salt or solvate thereof.

ID Embodiment 69. The compound of ID Embodiment 66, wherein J² is —C≡C—, or a salt or solvate thereof.

ID Embodiment 70. The compound of any one of ID Embodiments 1-69, wherein J³ is selected from the group consisting of cycloalkylenyl and heterocyclenyl, or a salt or solvate thereof.

ID Embodiment 71. The compound of ID Embodiment 70, wherein J³ is cycloalkylenyl, or a salt or solvate thereof.

ID Embodiment 72. The compound of ID Embodiment 70, wherein J³ is heterocyclenyl, or a salt or solvate thereof.

ID Embodiment 73. The compound of any one of ID Embodiments 1-69, wherein J³ is absent, or a salt or solvate thereof.

ID Embodiment 74. The compound of any one of ID Embodiments 1-73, wherein J⁴ is selected from the group consisting of alkylenyl, cycloalkylenyl, and heterocyclenyl, or a salt or solvate thereof.

ID Embodiment 75. The compound of ID Embodiment 74, wherein J⁴ is alkylenyl, or a salt or solvate thereof.

ID Embodiment 76. The compound of ID Embodiment 74, wherein J⁴ is cycloalkylenyl, or a salt or solvate thereof.

ID Embodiment 77. The compound of ID Embodiment 74, wherein J⁴ is heterocyclenyl, or a salt or solvate thereof.

ID Embodiment 78. The compound of any one of ID Embodiments 1-73, wherein J⁴ is absent, or a salt or solvate thereof.

ID Embodiment 79. The compound of any one of ID Embodiments 1-78, wherein:

J⁵ is selected from the group consisting of —O— and —N(H)—; and

B² is hydrogen, or salt or solvate thereof.

ID Embodiment 80. The compound of any one of ID Embodiments 1-77, wherein:

J⁵ is selected from the group consisting of —(CH₂)_m2— and —O—;

m2 is 0;

J⁴ is selected from the group consisting of J⁴-1, J⁴-2, J⁴-3, J⁴-4, J⁴-5, and J⁴-6, see above, wherein the bond designated with an “*” is attached to B²;

R⁷ is selected from the group consisting of hydrogen, halo, cyano, hydroxy, C₁-C₃ alkyl, and C₁-C₃ alkoxy; and

B² is hydrogen, or a salt or solvate thereof.

ID Embodiment 81. The compound of ID Embodiment 80, wherein J⁴ is J⁴-1, or a salt or solvate thereof.

ID Embodiment 82. The compound of ID Embodiment 80, wherein J⁴ is J⁴-2, or a salt or solvate thereof.

ID Embodiment 83. The compound of ID Embodiment 80, wherein J⁴ is J⁴-3, or a salt or solvate thereof.

ID Embodiment 84. The compound of ID Embodiment 80, wherein J⁴ is J⁴-4, or a salt or solvate thereof.

ID Embodiment 85. The compound of ID Embodiment 80, wherein J⁴ is J⁴-5, or a salt or solvate thereof.

ID Embodiment 86. The compound of ID Embodiment 80, wherein J⁴ is J⁴-6, or a salt or solvate thereof.

ID Embodiment 87. The compound of any one of ID Embodiments 1-86, wherein:

J⁵ is selected from the group consisting of —(CH₂)_m2— and —C(═O)—;

m2 is 0, 1, 2, or 3; and

B² is B¹-1, or a salt or solvate thereof.

ID Embodiment 88. The compound of ID Embodiment 87, wherein k1 is 0, or a salt or solvate thereof.

ID Embodiment 89. The compound of ID Embodiments 87 or 88, wherein m3 and n3 are 1, or a salt or solvate thereof.

ID Embodiment 90. The compound of any one of ID Embodiments 1-43, wherein:

J¹ is selected from the group consisting of:

wherein the bond marked with “*” is attached to X²;

J³ and J⁴ are absent;

J² is —(CH₂)_m1—;

m1 is 0;

J⁵ is —(CH₂)_m2—;

m2 is 0; and

B² is —CHO, or a salt or solvate thereof.

ID Embodiment 91. The compound of any one of ID Embodiments 1-43, wherein:

J¹, J³, and J⁴ are absent;

J² is —(CH₂)_m1—;

m1 is 0;

J⁵ is —(CH₂)_m2—;

m2 is 0; and

B² is B²-1, or a salt or solvate thereof.

ID Embodiment 92. The compound of any one of ID Embodiments 1-91, wherein R^3a is halo, or a salt or solvate thereof.

ID Embodiment 93. The compound of any one of ID Embodiments 1-91, wherein R^3a is C₁-C₄ alkyl, or a salt or solvate thereof.

ID Embodiment 94. The compound of any one of ID Embodiments 1-91, wherein R^3a is C₁-C₄ haloalkyl, or a salt or solvate thereof.

ID Embodiment 95. The compound of any one of ID Embodiments 1-91, wherein R^3a is selected from the group consisting of —Cl, —CH₃, and —CF₃, or a salt or solvate thereof.

ID Embodiment 96. The compound of any one of ID Embodiments 1-95, wherein Z¹ is —C(H)═, or a salt or solvate thereof.

ID Embodiment 97. The compound of any one of ID Embodiment 1-96, wherein Z² is —C(H)═, or a salt or solvate thereof.

ID Embodiment 98. The compound of ID Embodiment 1 of Formula XIII:

R^1a is selected from the group consisting of hydrogen and C₁-C₃ alkyl; and

R^5a, R^5b, R^5c and R^5d are each independently selected from the group consisting of hydrogen and halo.

ID Embodiment 99. The compound of ID Embodiment 1 of Formula XIV:

R^1a is selected from the group consisting of hydrogen and C₁-C₃ alkyl; and

R^5a, R^5b, R^5c and R^5d are each independently selected from the group consisting of hydrogen and halo.

ID Embodiment 100. The compound of ID Embodiments 98 or 99, wherein R^1a is methyl and R^5a, R^5b, R^5c, and R^5d are hydrogen.

IV. Kits of the Disclosure

In another embodiment, the present disclosure provides kits which comprise a Compound of the Disclosure (or a composition comprising a Compound of the Disclosure) packaged in a manner that facilitates its use to practice methods of the present disclosure. In one embodiment, the kit includes a Compound of the Disclosure (or a composition comprising a Compound of the Disclosure) packaged in a container, such as a sealed bottle or vessel, with a label affixed to the container or included in the kit that describes use of the compound or composition to practice the method of the disclosure. In one embodiment, the compound or composition is packaged in a unit dosage form. The kit further can include a device suitable for administering the composition according to the intended route of administration.

V. Definitions

The term “a disease or condition wherein degradation of androgen receptor (AR) provides a benefit” and the like pertains to a disease or condition in which the androgen receptor is important or necessary, e.g., for the onset, progress, expression of that disease or condition, or a disease or a condition which is known to be treated by an AR degrader. Examples of such conditions include, but are not limited to, a cancer. One of ordinary skill in the art is readily able to determine whether a compound treats a disease or condition mediated by an AR degrader for any particular cell type, for example, by assays which conveniently can be used to assess the activity of particular compounds.

The term “androgen receptor degrader,” “AR degrader,” and the like refer to a heterobifunctional small molecule that degrades AR protein. AR degraders contain a first ligand which binds to AR protein, a second ligand for an E3 ligase system, and a chemical linker that tethers the first and second ligands. Representative Compounds of the Disclosure that degrade AR protein are disclosed in Table 1.

The term “second therapeutic agent” refers to a therapeutic agent different from a Compound of the Disclosure and that is known to treat the disease or condition of interest. For example when a cancer is the disease or condition of interest, the second therapeutic agent can be a known chemotherapeutic drug, like taxol, or radiation, for example.

The term “disease” or “condition” denotes disturbances and/or anomalies that as a rule are regarded as being pathological conditions or functions, and that can manifest themselves in the form of particular signs, symptoms, and/or malfunctions. Compounds of the Disclosure are degraders of AR and can be used in treating or preventing diseases and conditions wherein degradation of AR provides a benefit.

As used herein, the terms “treat,” “treating,” “treatment,” and the like refer to eliminating, reducing, or ameliorating a disease or condition, and/or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated. The term “treat” and synonyms contemplate administering a therapeutically effective amount of a Compound of the Disclosure to a subject in need of such treatment. The treatment can be orientated symptomatically, for example, to suppress symptoms. It can be effected over a short period, be oriented over a medium term, or can be a long-term treatment, for example within the context of a maintenance therapy.

As used herein, the terms “prevent,” “preventing,” and “prevention” refer to a method of preventing the onset of a disease or condition and/or its attendant symptoms or barring a subject from acquiring a disease. As used herein, “prevent,” “preventing,” and “prevention” also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring a disease. The terms “prevent,” “preventing” and “prevention” may include “prophylactic treatment,” which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition.

The term “therapeutically effective amount” or “effective dose” as used herein refers to an amount of the active ingredient(s) that is(are) sufficient, when administered by a method of the disclosure, to efficaciously deliver the active ingredient(s) for the treatment of condition or disease of interest to a subject in need thereof. In the case of a cancer or other proliferation disorder, the therapeutically effective amount of the agent may reduce (i.e., retard to some extent or stop) unwanted cellular proliferation; reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., retard to some extent or stop) cancer cell infiltration into peripheral organs; inhibit (i.e., retard to some extent or stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve, to some extent, one or more of the symptoms associated with the cancer. To the extent the administered compound or composition prevents growth and/or kills existing cancer cells, it may be cytostatic and/or cytotoxic.

The term “container” means any receptacle and closure therefore suitable for storing, shipping, dispensing, and/or handling a pharmaceutical product.

The term “insert” means information accompanying a pharmaceutical product that provides a description of how to administer the product, along with the safety and efficacy data required to allow the physician, pharmacist, and patient to make an informed decision regarding use of the product. The package insert generally is regarded as the “label” for a pharmaceutical product.

“Concurrent administration,” “administered in combination,” “simultaneous administration,” and similar phrases mean that two or more agents are administered concurrently to the subject being treated. By “concurrently,” it is meant that each agent is administered either simultaneously or sequentially in any order at different points in time. However, if not administered simultaneously, it is meant that they are administered to a subject in a sequence and sufficiently close in time so as to provide the desired therapeutic effect and can act in concert. For example, a Compound of the Disclosure can be administered at the same time or sequentially in any order at different points in time as a second therapeutic agent. A Compound of the Disclosure and the second therapeutic agent can be administered separately, in any appropriate form and by any suitable route. When a Compound of the Disclosure and the second therapeutic agent are not administered concurrently, it is understood that they can be administered in any order to a subject in need thereof. For example, a Compound of the Disclosure can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapeutic agent treatment modality (e.g., radiotherapy), to a subject in need thereof. In various embodiments, a Compound of the Disclosure and the second therapeutic agent are administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 11 hours apart, 11 hours to 12 hours apart, no more than 24 hours apart or no more than 48 hours apart. In one embodiment, the components of the combination therapies are administered at about 1 minute to about 24 hours apart.

The use of the terms “a”, “an”, “the”, and similar referents in the context of describing the disclosure (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated. Recitation of ranges of values herein merely are intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended to better illustrate the disclosure and is not a limitation on the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.

The term “halo” as used herein by itself or as part of another group refers to —Cl, —F, —Br, or —I.

The term “nitro” as used herein by itself or as part of another group refers to —NO₂.

The term “cyano” as used herein by itself or as part of another group refers to —CN.

The term “hydroxy” as herein used by itself or as part of another group refers to —OH.

The term “alkyl” as used herein by itself or as part of another group refers to a straight- or branched-chain aliphatic hydrocarbon containing one to twelve carbon atoms, i.e., a C₁-C₁₂ alkyl, or the number of carbon atoms designated, e.g., a C₁ alkyl such as methyl, a C₂ alkyl such as ethyl, etc. In one embodiment, the alkyl is a C₁-C₁₀ alkyl. In another embodiment, the alkyl is a C₁-C₆ alkyl. In another embodiment, the alkyl is a C₁-C₄ alkyl. In another embodiment, the alkyl is a C₁-C₃ alkyl, i.e., methyl, ethyl, propyl, or isopropyl. Non-limiting exemplary C₁-C₁₂ alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

The term “optionally substituted alkyl” as used herein by itself or as part of another group refers to an alkyl group that is either unsubstituted or substituted with one, two, or three substituents, wherein each substituent is independently nitro, haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carbamate, carboxy, alkoxycarbonyl, carboxyalkyl, —N(R^56a)C(═O)R^56b, —N(R^56c)S(═O)₂R^56d, —C(═O)R⁵⁷, —S(═O)R^56e, or —S(═O)₂R⁵⁸; wherein:

R^56a is hydrogen or alkyl;

R^56b is alkyl, haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy)alkyl, (aryl)alkyl, (heteroaryl)alkyl, (amino)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted C₆-C₁₀ aryl, or optionally substituted heteroaryl;

R^56c is hydrogen or alkyl;

R^56d is alkyl, haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy)alkyl, (aryl)alkyl, (heteroaryl)alkyl, (amino)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted C₆-C₁₀ aryl, or optionally substituted heteroaryl;

R^56e is alkyl, haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy)alkyl, (aryl)alkyl, (heteroaryl)alkyl, (amino)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted C₆-C₁₀ aryl, or optionally substituted heteroaryl;

R⁵⁷ is haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy)alkyl, (aryl)alkyl, (heteroaryl)alkyl, (amino)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, or optionally substituted heteroaryl; and

R⁵⁸ is haloalkyl, optionally substituted cycloalkyl, alkoxy, (alkoxy)alkyl, (aryl)alkyl, (heteroaryl)alkyl, (amino)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycle, or optionally substituted heteroaryl. Non-limiting exemplary optionally substituted alkyl groups include —CH(CO₂Me)CH₂CO₂Me and —CH(CH₃)CH₂N(H)C(═O)O(CH₃)₃.

The term “alkenyl” as used herein by itself or as part of another group refers to an alkyl group containing one, two, or three carbon-to-carbon double bonds. In one embodiment, the alkenyl group is a C₂-C₆ alkenyl group. In another embodiment, the alkenyl group is a C₂-C₄ alkenyl group. In another embodiment, the alkenyl group has one carbon-to-carbon double bond. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

The term “optionally substituted alkenyl” as used herein by itself or as part of another refers to an alkenyl group that is either unsubstituted or substituted with one, two or three substituents, wherein each substituent is independently halo, nitro, cyano, hydroxy, amino (e.g., alkylamino, dialkylamino), haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclo. Non-limiting exemplary optionally substituted alkenyl groups include —CH═CHPh.

The term “alkynyl” as used herein by itself or as part of another group refers to an alkyl group containing one, two, or three carbon-to-carbon triple bonds. In one embodiment, the alkynyl is a C₂-C₆ alkynyl. In another embodiment, the alkynyl is a C₂-C₄ alkynyl. In another embodiment, the alkynyl has one carbon-to-carbon triple bond. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

The term “optionally substituted alkynyl” as used herein by itself or as part of another group refers to an alkynyl group that is either unsubstituted or substituted with one, two or three substituents, wherein each substituent is independently halo, nitro, cyano, hydroxy, amino, e.g., alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclo. Non-limiting exemplary optionally substituted alkynyl groups include —C≡CPh and —CH(Ph)C≡CH.

The term “haloalkyl” as used herein by itself or as part of another group refers to an alkyl group substituted by one or more fluorine, chlorine, bromine, and/or iodine atoms. In one embodiment, the alkyl is substituted by one, two, or three fluorine and/or chlorine atoms. In another embodiment, the alkyl is substituted by one, two, or three fluorine atoms. In another embodiment, the alkyl is a C₁-C₆ alkyl. In another embodiment, the alkyl is a C₁-C₄ alkyl. In another embodiment, the alkyl group is a C₁ or C₂ alkyl. Non-limiting exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl groups.

The terms “hydroxyalkyl” or “(hydroxy)alkyl” as used herein by themselves or as part of another group refer to an alkyl group substituted with one, two, or three hydroxy groups. In one embodiment, the alkyl is a C₁-C₆ alkyl. In another embodiment, the alkyl is a C₁-C₄ alkyl. In another embodiment, the alkyl is a C₁ or C₂ alkyl. In another embodiment, the hydroxyalkyl is a monohydroxyalkyl group, i.e., substituted with one hydroxy group. In another embodiment, the hydroxyalkyl group is a dihydroxyalkyl group, i.e., substituted with two hydroxy groups. Non-limiting exemplary (hydroxyl)alkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups, such as 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1,3-dihydroxyprop-2-yl.

The term “alkoxy” as used herein by itself or as part of another group refers to an alkyl group attached to a terminal oxygen atom. In one embodiment, the alkyl is a C₁-C₆ alkyl and resulting alkoxy is thus referred to as a “C₁-C₆ alkoxy.” In another embodiment, the alkyl is a C₁-C₄ alkyl group. Non-limiting exemplary alkoxy groups include methoxy, ethoxy, and tert-butoxy.

The term “haloalkoxy” as used herein by itself or as part of another group refers to a haloalkyl group attached to a terminal oxygen atom. In one embodiment, the haloalkyl group is a C₁-C₆ haloalkyl. In another embodiment, the haloalkyl group is a C₁-C₄ haloalkyl group. Non-limiting exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

The term “alkylthio” as used herein by itself or as part of another group refers to an alkyl group attached to a terminal sulfur atom. In one embodiment, the alkyl group is a C₁-C₄ alkyl group. Non-limiting exemplary alkylthio groups include —SCH₃, and —SCH₂CH₃.

The terms “alkoxyalkyl” or “(alkoxy)alkyl” as used herein by themselves or as part of another group refers to an alkyl group substituted with one alkoxy group. In one embodiment, the alkoxy is a C₁-C₆ alkoxy. In another embodiment, the alkoxy is a C₁-C₄ alkoxy. In another embodiment, the alkyl is a C₁-C₆ alkyl. In another embodiment, the alkyl is a C₁-C₄ alkyl. Non-limiting exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, iso-propoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl, tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, and pentyloxymethyl.

The term “heteroalkyl” as used by itself or part of another group refers to unsubstituted straight- or branched-chain aliphatic hydrocarbons containing from three to twenty chain atoms, i.e., 3- to 20-membered heteroalkyl, or the number of chain atoms designated, wherein at least one —CH₂— is replaced with at least one of —O—, —N(H)—, —N(C₁-C₄ alkyl)-, or —S—. The —O—, —N(H)—, —N(C₁-C₄ alkyl)-, or —S— can independently be placed at any interior position of the aliphatic hydrocarbon chain so long as each —O—, —N(H)—, —N(C₁-C₄ alkyl)-, and —S— group is separated by at least two —CH₂— groups. In one embodiment, one —CH₂— group is replaced with one —O— group. In another embodiment, two —CH₂— groups are replaced with two —O— groups. In another embodiment, three —CH₂— groups are replaced with three —O— groups. In another embodiment, four —CH₂— groups are replaced with four —O— groups. Non-limiting exemplary heteroalkyl groups include —CH₂OCH₃, —CH₂OCH₂CH₂CH₃, —CH₂CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₂OCH₂CH₃, —CH₂CH₂OCH₂CH₂OCH₂CH₂OCH₂CH₃.

The term “cycloalkyl” as used herein by itself or as part of another group refers to saturated and partially unsaturated, e.g., containing one or two double bonds, monocyclic, bicyclic, or tricyclic aliphatic hydrocarbons containing three to twelve carbon atoms, i.e., a C_3-12 cycloalkyl, or the number of carbons designated, e.g., a C₃ cycloalkyl such a cyclopropyl, a C₄ cycloalkyl such as cyclobutyl, etc. In one embodiment, the cycloalkyl is bicyclic, i.e., it has two rings. In another embodiment, the cycloalkyl is monocyclic, i.e., it has one ring. In another embodiment, the cycloalkyl is a C_3-8 cycloalkyl. In another embodiment, the cycloalkyl is a C_3-6 cycloalkyl, i.e., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In another embodiment, the cycloalkyl is a C₅ cycloalkyl, i.e., cyclopentyl. In another embodiment, the cycloalkyl is a C₆ cycloalkyl, i.e., cyclohexyl. Non-limiting exemplary C_3-12 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, and spiro[3.3]heptane.

The term “optionally substituted cycloalkyl” as used herein by itself or as part of another group refers to a cycloalkyl group that is either unsubstituted or substituted with one, two, or three substituents, wherein each substituent is independently halo, nitro, cyano, hydroxy, amino (e.g., —NH₂, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclo)alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, —N(R^56a)C(═O)R^56b, —N(R^56c)S(═O)₂R^56d, —C(═O)R⁵⁷, —S(═O)R^56e, —S(═O)₂R⁵⁸, or —OR⁵⁹, wherein R^56a, R^56b, R^56c, R^56d, R^56e, R⁵⁷, and R⁵⁸ are as defined in connection with the term “optionally substituted alkyl” and R⁵⁹ is (hydroxy)alkyl or (amino)alkyl. The term optionally substituted cycloalkyl also includes cycloalkyl groups having fused optionally substituted aryl or optionally substituted heteroaryl groups such as

Non-limiting exemplary optionally substituted cycloalkyl groups include:

The term “heterocyclo” as used herein by itself or as part of another group refers to saturated and partially unsaturated, e.g., containing one or two double bonds, monocyclic, bicyclic, or tricyclic groups containing three to eighteen ring members, i.e., a 3- to 18-membered heterocyclo, comprising one, two, three, or four heteroatoms. Each heteroatom is independently oxygen, sulfur, or nitrogen. Each sulfur atom is independently oxidized to give a sulfoxide, i.e., S(═O), or sulfone, i.e., S(═O)₂. The term heterocyclo includes groups wherein one or more —CH₂— groups is replaced with one or more —C(═O)— groups, including cyclic ureido groups such as imidazolidinyl-2-one, cyclic amide groups such as pyrrolidin-2-one or piperidin-2-one, and cyclic carbamate groups such as oxazolidinyl-2-one. The term heterocyclo also includes groups having fused optionally substituted aryl or optionally substituted heteroaryl groups such as indoline, indolin-2-one, 2,3-dihydro-1H-pyrrolo[2,3-c]pyridine, 2,3,4,5-tetrahydro-1H-benzo[d]azepine, or 1,3,4,5-tetrahydro-2H-benzo[d]azepin-2-one.

In one embodiment, the heterocyclo group is a 4- to 8-membered cyclic group containing one ring and one or two oxygen atoms, e.g., tetrahydrofuran or tetrahydropyran, or one or two nitrogen atoms, e.g., pyrrolidine, piperidine, or piperazine, or one oxygen and one nitrogen atom, e.g., morpholine, and, optionally, one —CH₂— group is replaced with one —C(═O)— group, e.g., pyrrolidin-2-one or piperazin-2-one. In another embodiment, the heterocyclo group is a 5- to 8-membered cyclic group containing one ring and one or two nitrogen atoms and, optionally, one —CH₂— group is replaced with one —C(═O)— group. In another embodiment, the heterocyclo group is a 5- or 6-membered cyclic group containing one ring and one or two nitrogen atoms and, optionally, one —CH₂— group is replaced with one —C(═O)— group. In another embodiment, the heterocyclo group is a 8- to 12-membered cyclic group containing two rings and one or two nitrogen atoms. The heterocyclo can be linked to the rest of the molecule through any available carbon or nitrogen atom. Non-limiting exemplary heterocyclo groups include:

The term “optionally substituted heterocyclo” as used herein by itself or part of another group refers to a heterocyclo group that is either unsubstituted or substituted with one to four substituents, wherein each substituent is independently halo, nitro, cyano, hydroxy, amino, (e.g., —NH₂, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclo)alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, —N(R^56a)C(═O)R^56b, —N(R^56c)S(═O)₂R^56d, —C(═O)R⁵⁷, —S(═O)R^56e, —S(═O)₂R⁵⁸, or —OR⁵⁹, wherein R^56a, R^56b, R^56c, R^56d, R^56e, R⁵⁷, R⁵⁸, and R⁵⁹ are as defined in connection with the term “optionally substituted cycloalkyl.” Substitution may occur on any available carbon or nitrogen atom of the heterocyclo group. Non-limiting exemplary optionally substituted heterocyclo groups include:

In one embodiment, the heterocyclo group is a spiroheterocyclo. The term “spiroheterocyclo” as used herein by itself or part of another group refers to an optionally substituted heterocyclo group containing seven to eighteen ring members, wherein:

(i) a first and second ring are connected through a quaternary carbon atom, i.e., a spirocarbon;

(ii) the first ring is an optionally substituted mono- or bicyclic heterocyclo containing a nitrogen atom; and

(iii) the second ring is either:

(a) an optionally substituted mono- or bicyclic cycloalkyl; or

(b) an optionally substituted mono- or bicyclic heterocyclo containing a nitrogen atom.

In one embodiment, the first ring is an optionally substituted monocyclic 4- to 9-membered heterocyclo containing a nitrogen atom. In another embodiment, the second ring is an optionally substituted monocyclic C_3-8 cycloalkyl. In another embodiment, the second ring is a monocyclic C_3-8 cycloalkyl substituted with a hydroxy group. In another embodiment, the second ring is an optionally substituted monocyclic 4- to 9-membered heterocyclo containing a nitrogen atom. Non-limiting exemplary spiroheterocyclo groups include:

The term “aryl” as used herein by itself or as part of another group refers to an aromatic ring system having six to fourteen carbon atoms, i.e., C₆-C₁₄ aryl. Non-limiting exemplary aryl groups include phenyl (abbreviated as “Ph”), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. In one embodiment, the aryl group is phenyl or naphthyl. In another embodiment, the aryl group is phenyl.

The term “optionally substituted aryl” as used herein by itself or as part of another group refers to aryl that is either unsubstituted or substituted with one to five substituents, wherein the substituents are each independently halo, nitro, cyano, hydroxy, amino, (e.g., —NH₂, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclo)alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, —N(R^56a)C(═O)R^56b, —N(R^56c)S(═O)₂R^56d, —C(═O)R⁵⁷, —S(═O)R^56e, —S(═O)₂R⁵⁸, or —OR⁵⁹, wherein R^56a, R^56b, R^56c, R^56d, R^56e, R⁵⁷, R⁵⁸, and R⁵⁹ are as defined in connection with the term “optionally substituted cycloalkyl.”

In one embodiment, the optionally substituted aryl is an optionally substituted phenyl. In another embodiment, the optionally substituted phenyl has four substituents. In another embodiment, the optionally substituted phenyl has three substituents. In another embodiment, the optionally substituted phenyl has two substituents. In another embodiment, the optionally substituted phenyl has one substituent. Non-limiting exemplary optionally substituted aryl groups include 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,6-di-fluorophenyl, 2,6-di-chlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-di-methoxyphenyl, 3,5-di-fluorophenyl 3,5-di-methylphenyl, 3,5-dimethoxy, 4-methylphenyl, 2-fluoro-3-chlorophenyl, 3-chloro-4-fluorophenyl, and 2-phenylpropan-2-amine. The term optionally substituted aryl includes aryl groups having fused optionally substituted cycloalkyl groups and fused optionally substituted heterocyclo groups. Non-limiting examples include: 2,3-dihydro-1H-inden-1-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, 1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl, 1,2,3,4-tetrahydroisoquinolin-1-yl, and 2-oxo-2,3,4,5-tetrahydro-1H-benzo[d]azepin-1-yl.

The term “heteroaryl” as used herein by itself or as part of another group refers to monocyclic and bicyclic aromatic ring systems having five to 14 fourteen ring members, i.e., a 5- to 14-membered heteroaryl, comprising one, two, three, or four heteroatoms. Each heteroatom is independently oxygen, sulfur, or nitrogen. In one embodiment, the heteroaryl has three heteroatoms. In another embodiment, the heteroaryl has two heteroatoms. In another embodiment, the heteroaryl has one heteroatom. In another embodiment, the heteroaryl is a 5- to 10-membered heteroaryl. In another embodiment, the heteroaryl has 5 ring atoms, e.g., thienyl, a 5-membered heteroaryl having four carbon atoms and one sulfur atom. In another embodiment, the heteroaryl has 6 ring atoms, e.g., pyridyl, a 6-membered heteroaryl having five carbon atoms and one nitrogen atom. Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, and phenoxazinyl. In one embodiment, the heteroaryl is chosen from thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl), isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl) and isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl). The term heteroaryl also includes N-oxides. A non-limiting exemplary N-oxide is pyridyl N-oxide.

The term “optionally substituted heteroaryl” as used herein by itself or as part of another group refers to a heteroaryl that is either unsubstituted or substituted with one to four substituents, wherein the substituents are independently halo, nitro, cyano, hydroxy, amino, (e.g., —NH₂, alkylamino, dialkylamino, aralkylamino, hydroxyalkylamino, or (heterocyclo)alkylamino), heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, (heteroaryl)alkyl, —N(R^56a)C(═O)R^56b, —N(R^56c)S(═O)₂R^56d, —C(═O)R⁵⁷, —S(═O)R^56e, —S(═O)₂R⁵⁸, or —OR⁵⁹, wherein R^56a, R^56b, —R^56c, R^56d, R⁵⁶, R⁵⁷, R⁵⁸, and R⁵⁹ are as defined in connection with the term “optionally substituted cycloalkyl.”

In one embodiment, the optionally substituted heteroaryl has two substituents. In another embodiment, the optionally substituted heteroaryl has one substituent. Any available carbon or nitrogen atom can be substituted.

The term “aryloxy” as used herein by itself or as part of another group refers to an optionally substituted aryl attached to a terminal oxygen atom. A non-limiting exemplary aryloxy group is PhO—.

The term “heteroaryloxy” as used herein by itself or as part of another group refers to an optionally substituted heteroaryl attached to a terminal oxygen atom. A non-limiting exemplary aryloxy group is pyridyl-O—.

The term “aralkyloxy” as used herein by itself or as part of another group refers to an aralkyl attached to a terminal oxygen atom. A non-limiting exemplary aralkyloxy group is PhCH₂O—.

The term “(cyano)alkyl” as used herein by itself or as part of another group refers to an alkyl substituted with one, two, or three cyano groups. In one embodiment, the alkyl is substituted with one cyano group. In another embodiment, the alkyl is a C₁-C₆ alkyl In another embodiment, the alkyl is a C₁-C₄ alkyl. Non-limiting exemplary (cyano)alkyl groups include —CH₂CH₂CN and —CH₂CH₂CH₂CN.

The term “(cycloalkyl)alkyl” as used herein by itself or as part of another group refers to an alkyl substituted with one or two optionally substituted cycloalkyl groups. In one embodiment, the cycloalkyl group(s) is an optionally substituted C₃-C₆ cycloalkyl. In another embodiment, the alkyl is a C₁-C₆ alkyl. In another embodiment, the alkyl is a C₁-C₄ alkyl. In another embodiment, the alkyl is a C₁ or C₂ alkyl. In another embodiment, the alkyl is substituted with one optionally substituted cycloalkyl group. In another embodiment, the alkyl is substituted with two optionally substituted cycloalkyl groups. Non-limiting exemplary (cycloalkyl)alkyl groups include:

The term “sulfonamido” as used herein by itself or as part of another group refers to a radical of the formula —SO₂NR^50aR^50b, wherein R^50a and R^50b are each independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl; or R^50a and R^50b taken together with the nitrogen to which they are attached form a 3- to 8-membered optionally substituted heterocyclo group. Non-limiting exemplary sulfonamido groups include —SO₂NH₂, —SO₂N(H)CH₃, and —SO₂N(H)Ph.

The term “alkylcarbonyl” as used herein by itself or as part of another group refers to a carbonyl group, i.e., —C(═O)—, substituted by an alkyl group. In one embodiment, the alkyl is a C₁-C₄ alkyl. A non-limiting exemplary alkylcarbonyl group is —COCH₃.

The term “arylcarbonyl” as used herein by itself or as part of another group refers to a carbonyl group, i.e., —C(═O)—, substituted by an optionally substituted aryl group. A non-limiting exemplary arylcarbonyl group is —COPh.

The term “alkylsulfonyl” as used herein by itself or as part of another group refers to a sulfonyl group, i.e., —SO₂—, substituted by an alkyl group. A non-limiting exemplary alkylsulfonyl group is —SO₂CH₃.

The term “arylsulfonyl” as used herein by itself or as part of another group refers to a sulfonyl group, i.e., —SO₂—, substituted by an optionally substituted aryl group. A non-limiting exemplary arylsulfonyl group is —SO₂Ph.

The term “mercaptoalkyl” as used herein by itself or as part of another group refers to an alkyl substituted by a —SH group.

The term “carboxy” as used by itself or as part of another group refers to a radical of the formula —C(═O)OH.

The term “ureido” as used herein by itself or as part of another group refers to a radical of the formula —NR^51a—C(═O)—NR^51bR^51c, wherein R^51a is hydrogen or alkyl; and R^51b and R^51c are each independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl, or R^51b and R^51c taken together with the nitrogen to which they are attached form a 4- to 8-membered optionally substituted heterocyclo group. Non-limiting exemplary ureido groups include —NH—C(C═O)—NH₂ and —NH—C(C═O)—NHCH₃.

The term “guanidino” as used herein by itself or as part of another group refers to a radical of the formula —NR^52a—C(═NR⁵³)—NR^52bR^52c, wherein R^52a is hydrogen or alkyl; R^52b and R^53c are each independently hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl; or R^52b and R^52c taken together with the nitrogen to which they are attached form a 4- to 8-membered optionally substituted heterocyclo group; and R⁵³ is hydrogen, alkyl, cyano, alkylsulfonyl, alkylcarbonyl, carboxamido, or sulfonamido. Non-limiting exemplary guanidino groups include —NH—C(C═NH)—NH₂, —NH—C(C═NCN)—NH₂, and —NH—C(C═NH)—NHCH₃.

The term “(heterocyclo)alkyl” as used herein by itself or as part of another group refers to an alkyl substituted with one, two, or three optionally substituted heterocyclo groups. In one embodiment, the alkyl is substituted with one optionally substituted 5- to 8-membered heterocyclo group. In another embodiment, alkyl is a C₁-C₆ alkyl. In another embodiment, alkyl is a C₁-C₄ alkyl. The heterocyclo group can be linked to the alkyl group through a carbon or nitrogen atom. Non-limiting exemplary (heterocyclo)alkyl groups include:

The term “carbamate” as used herein by itself or as part of another group refers to a radical of the formula —NR^54a—C(═O)—OR^54b, wherein R^54a is hydrogen or alkyl, and R^54b is hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, or optionally substituted heteroaryl. A non-limiting exemplary carbamate group is —NH—(C═O)—OtBu.

The term “(heteroaryl)alkyl” as used herein by itself or as part of another group refers to an alkyl substituted with one or two optionally substituted heteroaryl groups. In one embodiment, the alkyl group is substituted with one optionally substituted 5- to 14-membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5- to 14-membered heteroaryl groups. In another embodiment, the alkyl group is substituted with one optionally substituted 5- to 9-membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5- to 9-membered heteroaryl groups. In another embodiment, the alkyl group is substituted with one optionally substituted 5- or 6-membered heteroaryl group. In another embodiment, the alkyl group is substituted with two optionally substituted 5- or 6-membered heteroaryl groups. In one embodiment, the alkyl group is a C₁-C₆ alkyl. In another embodiment, the alkyl group is a C₁-C₄ alkyl. In another embodiment, the alkyl group is a C₁ or C₂ alkyl. Non-limiting exemplary (heteroaryl)alkyl groups include:

The term “(amino)(heteroaryl)alkyl” as used herein by itself or as part of another group refers to an alkyl group substituted with one optionally substituted heteroaryl group and one amino group. In one embodiment, the heteroaryl is an optionally substituted 5- to 9-membered heteroaryl group. In another embodiment, the heteroaryl is an optionally substituted 5- or 6-membered heteroaryl group. In one embodiment, the alkyl is a C₁-C₆ alkyl. In another embodiment, the alkyl is a C₁-C₄ alkyl. In another embodiment, the alkyl is a C₁ or C₂ alkyl. A non-limiting exemplary (amino)(heteroaryl)alkyl group is:

The terms “aralkyl” or “(aryl)alkyl” as used herein by themselves or as part of another group refers to an alkyl substituted with one, two, or three optionally substituted aryl groups. In one embodiment, the alkyl is substituted with one optionally substituted aryl group. In another embodiment, the alkyl is substituted with two optionally substituted aryl groups. In one embodiment, the aryl is an optionally substituted phenyl or optionally substituted naphthyl. In another embodiment, the aryl is an optionally substituted phenyl. In one embodiment, the alkyl is a C₁-C₆ alkyl. In another embodiment, the alkyl is a C₁-C₄ alkyl. In another embodiment, the alkyl is a C₁ or C₂ alkyl. Non-limiting exemplary (aryl)alkyl groups include benzyl, phenethyl, —CHPh₂, and —CH(4-F-Ph)₂.

The term “amido” as used herein by itself or as part of another group refers to a radical of formula —C(═O)NR^60aR^60b, wherein R^60a and R^60b are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, haloalkyl, (alkoxy)alkyl, (hydroxy)alkyl, (cyano)alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, optionally substituted heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, or (heteroaryl)alkyl; or R^60a and R^60b taken together with the nitrogen to which they are attached from a 4- to 8-membered optionally substituted heterocyclo group. In one embodiment, R^60a and R^60b are each independently hydrogen or C₁-C₆ alkyl.

The term “(amido)(aryl)alkyl” as used herein by itself or as part of another group refers to an alkyl group substituted with one amido group and one optionally substituted aryl group. In one embodiment, the aryl group is an optionally substituted phenyl. In one embodiment, the alkyl is a C₁-C₆ alkyl. In another embodiment, the alkyl is a C₁-C₄ alkyl. Non-limiting exemplary (amido)(aryl)alkyl groups include:

The term “(amino)(aryl)alkyl” as used herein by itself or as part of another group refers to an alkyl group substituted with one amino group and one optionally substituted aryl group. In one embodiment, the amino group is —NH₂, alkylamino, or dialkylamino. In one embodiment, the aryl group is an optionally substituted phenyl. In one embodiment, the alkyl is a C₁-C₆ alkyl. In another embodiment, the alkyl is a C₁-C₄ alkyl. Non-limiting exemplary (amino)(aryl)alkyl groups include:

The term “amino” as used by itself or as part of another group refers to a radical of the formula —NR^55aR^55b, wherein R^55a and R^55b are independently hydrogen, optionally substituted alkyl, haloalkyl, (hydroxy)alkyl, (alkoxy)alkyl, (amino)alkyl, heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclo, optionally substituted aryl, optionally substituted heteroaryl, (aryl)alkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, or (heteroaryl)alkyl.

In one embodiment, the amino is —NH₂.

In another embodiment, the amino is an “alkylamino,” i.e., an amino group wherein R^55a is C_1-6 alkyl and R^55b is hydrogen. In one embodiment, R^55a is C₁-C₄ alkyl. Non-limiting exemplary alkylamino groups include —N(H)CH₃ and —N(H)CH₂CH₃.

In another embodiment, the amino is a “dialkylamino,” i.e., an amino group wherein R^55a and R^55b are each independently C_1-6 alkyl. In one embodiment, R^55a and R^55b are each independently C₁-C₄ alkyl. Non-limiting exemplary dialkylamino groups include —N(CH₃)₂ and —N(CH₃)CH₂CH(CH₃)₂.

In another embodiment, the amino is a “hydroxyalkylamino,” i.e., an amino group wherein R^55a is (hydroxyl)alkyl and R^55b is hydrogen or C₁-C₄ alkyl.

In another embodiment, the amino is a “cycloalkylamino,” i.e., an amino group wherein R^55a is optionally substituted cycloalkyl and R^55b is hydrogen or C₁-C₄ alkyl.

In another embodiment, the amino is a “aralkylamino,” i.e., an amino group wherein R^55a is aralkyl and R^55b is hydrogen or C₁-C₄ alkyl. Non-limiting exemplary aralkylamino groups include —N(H)CH₂Ph, —N(H)CHPh₂, and —N(CH₃)CH₂Ph.

In another embodiment, the amino is a “(cycloalkyl)alkylamino,” i.e., an amino group wherein R^55a is (cycloalkyl)alkyl and R^55b is hydrogen or C₁-C₄ alkyl. Non-limiting exemplary (cycloalkyl)alkylamino groups include:

In another embodiment, the amino is a “(heterocyclo)alkylamino,” i.e., an amino group wherein R^55a is (heterocyclo)alkyl and R^55b is hydrogen or C₁-C₄ alkyl. Non-limiting exemplary (heterocyclo)alkylamino groups include:

The term “(amino)alkyl” as used herein by itself or as part of another group refers to an alkyl substituted with one amino group. In one embodiment, the amino group is —NH₂. In one embodiment, the amino group is an alkylamino. In another embodiment, the amino group is a dialkylamino. In another embodiment, the alkyl is a C₁-C₆ alkyl. In another embodiment, the alkyl is a C₁-C₄ alkyl. Non-limiting exemplary (amino)alkyl groups include —CH₂NH₂, —CH₂CH₂N(H)CH₃, —CH₂CH₂N(CH₃)₂, CH₂N(H)cyclopropyl, —CH₂N(H)cyclobutyl, and —CH₂N(H)cyclohexyl, and —CH₂CH₂CH₂N(H)CH₂Ph and —CH₂CH₂CH₂N(H)CH₂(4-CF₃-Ph).

The term “heteroarylenyl” as used herein by itself or part of another group refers to a divalent form of an optionally substituted heteroaryl group, e.g., a 5- to 9-membered heteroarylenyl. In one embodiment, the heteroarylenyl is a 6-membered heteroarylenyl, e.g., heteroarylenyl derived from pyridine. In one embodiment, the heteroarylenyl is a bicyclic 9-membered heteroarylenyl. Exemplary non-limiting exemplary heteroarylenyl groups include:

In the present disclosure, the term “alkylenyl” as used herein by itself or part of another group refers to a divalent form of an alkyl group, wherein the alkyl group is either unsubstituted or substituted with one or two groups independently selected from the group consisting of optionally substituted phenyl and optionally substituted 5- or 6-membered heteroaryl. In one embodiment, the alkylenyl is a divalent form of a C_1-12 alkyl, i.e., a C₁-C₁₂ alkylenyl. In one embodiment, the alkylenyl is a divalent form of a C_1-10 alkyl, i.e., a C₁-C₁₀ alkylenyl. In one embodiment, the alkylenyl is a divalent form of a C_1-8 alkyl, i.e., a C₁-C₈ alkylenyl. In one embodiment, the alkylenyl is a divalent form of an unsubstituted C_1-6 alkyl, i.e., a C₁-C₆ alkylenyl. In another embodiment, the alkylenyl is a divalent form of an unsubstituted C_1-4 alkyl, i.e., a C₁-C₈ alkylenyl. In another embodiment, the alkylenyl is a divalent form of a C_1-4 alkyl substituted with one or two optionally substituted phenyl groups. Non-limiting exemplary alkylenyl groups include —CH₂—, —CH₂CH₂—, —CH(Ph)-, —CH(Ph)CH₂—, —CH₂CH₂CH₂—, —CH(Ph)CH₂CH₂—, —CH₂(CH₂)₂CH₂—, —CH(CH₂)₃CH₂—, and —CH₂(CH₂)₄CH₂—.

The term “heteroalkylenyl” as used herein by itself or part of another group refers to a divalent form of a heteroalkyl group. In one embodiment, the heteroalkylenyl is a divalent form of a 3- to 20-membered heteroalkyl, i.e., a 3- to 20-membered heteroalkylenyl. In another embodiment, the heteroalkylenyl is a divalent form of a 3- to 10-membered heteroalkyl, i.e., a 3- to 10-membered heteroalkylenyl. In another embodiment, the heteroalkylenyl is a divalent form of a 3- to 8-membered heteroalkyl, i.e., a 3- to 8-membered heteroalkylenyl. In another embodiment, the heteroalkylenyl is a divalent form of a 3- to 6-membered heteroalkyl, i.e., a 3- to 6-membered heteroalkylenyl. In another embodiment, the heteroalkylenyl is a divalent form of a 3- or 4-membered heteroalkyl, i.e., a 3- or 4-membered heteroalkylenyl. In another embodiment, the heteroalkylenyl is a radical of the formula —(CH₂CH₂O)_u1— wherein u₁ is 1, 2, 3, 4, 5, or 6. Non-limiting exemplary heteroalkylenyl groups include —CH₂OCH₂—, —CH₂CH₂OCH₂CH₂O—, —CH₂OCH₂CH₂CH₂—, and —CH₂CH₂OCH₂CH₂OCH₂CH₂O—.

The term “heterocyclenyl” as used herein by itself or part of another group refers to a divalent form of an optionally substituted heterocyclo group. In another embodiment, the heterocyclenyl is a divalent form of a 4- to 14-membered heterocyclo group, i.e., a 4- to 14-membered heterocyclenyl. In another embodiment, the heterocyclenyl is a divalent form of a 4- to 10-membered heterocyclo group, i.e., a 4- to 10-membered heterocyclenyl. In another embodiment, the heterocyclenyl is a divalent form of a 4- to 8-membered heterocyclo group, i.e., a 4- to 8-membered heterocyclenyl. In one embodiment, the heterocyclenyl is a divalent form of an optionally substituted azetidine. In another embodiment, the heterocyclenyl is a divalent form of an optionally substituted piperidinyl. In another embodiment, the heterocyclenyl is a divalent form of an optionally substituted piperazinyl. Non-limiting exemplary heterocyclenyl groups include:

In another embodiment, the heterocyclenyl is a spiroheterocyclenyl.

The term “spiroheterocyclenyl” as used herein by itself or part of another group refers to a divalent form of a spiroheterocyclo. Non-limiting exemplary spiroheterocyclenyl groups include:

The term “cycloalkylenyl” as used herein by itself or part of another group refers to a divalent form of an optionally substituted C₄-C₆ cycloalkyl group. In one embodiment, the cycloalkylenyl is a 4-membered cycloalkylenyl. In another embodiment, the cycloalkylenyl is a 5-membered cycloalkylenyl. In another embodiment, the cycloalkylenyl is a 6-membered cycloalkylenyl. Non-limiting exemplary groups include:

The term “phenylenyl” as used herein by itself or part of another group refers to a divalent form of an optionally substituted phenyl group. Non-limiting examples include:

The present disclosure encompasses any of the Compounds of the Disclosure being isotopically-labelled (i.e., radiolabeled) by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as ²H (or deuterium (D)), ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively, e.g., ³H, ¹¹C, and ¹⁴C. In one embodiment, provided is a composition wherein substantially all of the atoms at a position within the Compound of the Disclosure are replaced by an atom having a different atomic mass or mass number. In another embodiment, provided is a composition wherein a portion of the atoms at a position within the Compound of the disclosure are replaced, i.e., the Compound of the Disclosure is enriched at a position with an atom having a different atomic mass or mass number.” Isotopically-labelled Compounds of the Disclosure can be prepared by methods known in the art.

As noted above, Compounds of the Disclosure contain one or more asymmetric carbon atoms and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present disclosure encompasses the use of all such possible forms, as well as their racemic and resolved forms and mixtures thereof. The individual enantiomers can be separated according to methods known in the art in view of the present disclosure. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers. All tautomers are also encompassed by the present disclosure.

As used herein, the term “stereoisomers” is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).

The term “chiral center” or “asymmetric carbon atom” refers to a carbon atom to which four different groups are attached.

The terms “enantiomer” and “enantiomeric” refer to a molecule that cannot be superimposed on its mirror image and hence is optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers and which mixture is optically inactive. In one embodiment, Compounds of the Disclosure are racemic.

The term “absolute configuration” refers to the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description, e.g., R or S.

The stereochemical terms and conventions used in the specification are meant to be consistent with those described in Pure & Appl. Chem 68:2193 (1996), unless otherwise indicated.

The term “enantiomeric excess” or “ee” refers to a measure for how much of one enantiomer is present compared to the other. For a mixture of R and S enantiomers, the percent enantiomeric excess is defined as |R−S|*100, where R and S are the respective mole or weight fractions of enantiomers in a mixture such that R+S=1. With knowledge of the optical rotation of a chiral substance, the percent enantiomeric excess is defined as ([α]_obs/[α]_max)*100, where [α]_obs is the optical rotation of the mixture of enantiomers and [α]_max is the optical rotation of the pure enantiomer. Determination of enantiomeric excess is possible using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography or optical polarimetry.

The term “about,” as used herein, includes the recited number ±10%. Thus, “about 10” means 9 to 11.

EXAMPLES

Example 1

Synthesis of 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 1)

Step 1: Synthesis of 2-chloro-4-(2,8-diazaspiro[4.5]decan-2-yl)benzonitrile

2-Chloro-4-fluorobenzonitrile and tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate were dissolved in DMSO. To this solution was added DIPEA (5 eq.), and the reaction mixture was stirred at 100° C. for 4 h. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated, washed with water, and dried over Na₂SO₄. The Boc protected intermediate was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. 2-Chloro-4-(2,8-diazaspiro[4.5]decan-2-yl)benzonitrile was obtained by removing the Boc group using TFA in DCM. ESI-MS: 275.12.

Step 2: Synthesis of 2-chloro-4-(8-(4-(piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile

2-Chloro-4-(2,8-diazaspiro[4.5]decan-2-yl)benzonitrile and 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid were dissolved in DMF. To this solution was added DIPEA (5 eq.) and HATU (1.2 eq.), and the reaction mixture was stirred at r.t. for 1 h. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated, washed with water, and dried over Na₂SO₄. The Boc protected compound was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. 2-Chloro-4-(8-(4-(piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile was obtained by removing the Boc group using TFA in DCM. ESI-MS: 463.21.

Step 3: Synthesis of 4-(8-(4-(4-(azetidin-3-ylmethyl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)-2-chlorobenzonitrile

To a solution of 2-chloro-4-(8-(4-(piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile and tert-butyl 3-(bromomethyl)azetidine-1-carboxylate in CH₃CN was added K₂CO₃ (2 eq.) and KI (20%). The reaction mixture was refluxed for 4 h. All volatiles were removed and the residue was chromatographed on silica gel to afford the intermediate Boc protected compound. 4-(8-(4-(4-(Azetidin-3-ylmethyl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)-2-chlorobenzonitrile was obtained by removing the Boc group using TFA in DCM. ESI-MS: 532.27.

Step 4: Synthesis of 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 1)

To a solution of 4-(8-(4-(4-(azetidin-3-ylmethyl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)-2-chlorobenzonitrile and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione in DMSO was added DIPEA (5 eq.). The reaction mixture was stirred at 100° C. for 12 h. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated, washed with water, and dried over Na₂SO₄. 2-Chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (d, J=4.8 Hz, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.60-7.58 (m, 1H), 7.34 (d, J=8.5 Hz, 2H), 7.08-7.04 (m, 2H), 6.81 (d, J=2.1 Hz, 1H), 6.72 (d, J=2.4 Hz, 1H), 6.67 (dd, J=8.4, 2.1 Hz, 1H), 6.57 (dd, J=8.9, 2.3 Hz, 1H), 5.09-5.03 (m, 1H), 4.26 (t, J=8.2 Hz, 2H), 3.87 (dd, J=8.6, 5.6 Hz, 4H), 3.60 (t, J=10.5 Hz, 6H), 3.43 (dt, J=24.9, 7.9 Hz, 8H), 2.92-2.84 (m, 1H), 2.63-2.53 (m, 3H), 2.05-1.99 (m, 1H), 1.92 (t, J=7.0 Hz, 2H), 1.55 (t, J=5.8 Hz, 5H), 1.26 (q, J=6.3 Hz, 1H). LC-MS (ESI) m/z (M+H)⁺: 789.48; calcd: 789.33; >95% purity.

Example 2

Synthesis of 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 3)

Step 1: Synthesis of 2-chloro-4-(8-(4-(4-(piperidin-4-yl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile

To a solution of 2-chloro-4-(8-(4-(piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile and tert-butyl 4-oxopiperidine-1-carboxylate in DCE was added NaBH(OAc)₃ (1.5 eq.), AcOH, and TEA. The reaction mixture was stirred at r.t. for 6 h. All volatiles were removed and the residue was chromatographed on silica gel to afford the Boc protected compound. 2-Chloro-4-(8-(4-(4-(piperidin-4-yl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile was obtained by removing the Boc group using TFA in DCM. ESI-MS: 546.29.

Step 2: Synthesis of 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 3)

To a solution of 2-chloro-4-(8-(4-(4-(piperidin-4-yl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione in DMSO was added DIPEA (5 eq.). The reaction mixture was stirred at 100° C. for 12 h. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated, washed with water, and dried over Na₂SO₄. 2-Chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.43 (s, 1H), 7.33 (d, J=8.4 Hz, 3H), 7.04 (d, J=8.5 Hz, 2H), 6.73 (s, 1H), 6.58 (dd, J=8.9, 2.3 Hz, 1H), 5.09 (dd, J=12.9, 5.4 Hz, 1H), 4.27 (d, J=13.2 Hz, 2H), 3.96 (d, J=12.6 Hz, 2H), 3.76-3.48 (m, 8H), 3.28 (s, 2H), 3.24-2.86 (m, 7H), 2.64-2.54 (m, 2H), 2.26-2.16 (m, 2H), 2.08-2.00 (m, 1H), 1.93 (t, J=7.0 Hz, 2H), 1.73 (qd, J=12.3, 4.0 Hz, 2H), 1.55 (t, J=5.9 Hz, 4H), 1.30-1.19 (m, 1H). LC-MS (ESI) m/z (M+H)⁺: 803.41; calcd: 803.34; >95% purity.

Example 3

Synthesis of 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 44)

Step 1: Synthesis of 4-(2-(3-chloro-4-cyanophenyl)-2,8-diazaspiro[4.5]decan-8-yl)benzoic acid

2-Chloro-4-(2,8-diazaspiro[4.5]decan-2-yl)benzonitrile and tert-butyl 4-bromobenzoate were dissolved in dioxane at rt. To this solution was added Pd₂(dba)₃ (10%), xantphos (10%), and Cs₂CO₃ (3 eq.), and the reaction mixture was stirred at 100° C. for 6 h. The t-Bu ester compound was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. 4-(2-(3-Chloro-4-cyanophenyl)-2,8-diazaspiro[4.5]decan-8-yl)benzoic acid was obtained by removing the t-Bu group using TFA in DCM. ESI-MS: 395.14.

Step 2: Synthesis of 2-chloro-4-(8-(4-(piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile

4-(2-(3-Chloro-4-cyanophenyl)-2,8-diazaspiro[4.5]decan-8-yl)benzoic acid and tert-butyl piperazine-1-carboxylate were dissolved in DMF. To this solution was added DIPEA (5 eq.) and HATU (1.2 eq.), and the reaction mixture was stirred at r.t. for 1 h. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated, washed with water, and dried over Na₂SO₄. The Boc protected compound was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. 2-Chloro-4-(8-(4-(piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile was obtained by removing the Boc group using TFA in DCM. ESI-MS: 463.21.

Step 3: Synthesis of 2-chloro-4-(8-(4-(4-(piperidin-4-ylmethyl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile

To a solution of 2-chloro-4-(8-(4-(piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile and tert-butyl 4-(bromomethyl)piperidine-1-carboxylate in CH₃CN was added K₂CO₃ (2 eq.) and KI (20%). The reaction mixture was refluxed for 4 h. All volatiles were removed and the residue was chromatographed on silica gel to afford the intermediate Boc protected compound. 2-Chloro-4-(8-(4-(4-(piperidin-4-ylmethyl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile was obtained by removing the Boc group using TFA in DCM. ESI-MS: 560.30.

Step 4: Synthesis of 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 44)

To a solution of 2-chloro-4-(8-(4-(4-(piperidin-4-ylmethyl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione in DMSO was added DIPEA (5 eq.). The reaction mixture was stirred at 100° C. for 12 h. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated, washed with water, and dried over Na₂SO₄. 2-Chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.37 (d, J=8.6 Hz, 3H), 7.27 (dd, J=8.7, 2.2 Hz, 1H), 7.03 (d, J=8.4 Hz, 2H), 6.74 (d, J=2.1 Hz, 1H), 6.59 (dd, J=8.9, 2.2 Hz, 1H), 5.08 (dd, J=12.8, 5.4 Hz, 2H), 4.09 (d, J=13.1 Hz, 2H), 3.42 (q, J=6.0, 5.3 Hz, 4H), 3.28 (d, J=6.8 Hz, 4H), 3.11-2.84 (m, 8H), 2.58 (ddd, J=18.6, 13.4, 5.9 Hz, 2H), 2.19-1.99 (m, 2H), 1.94-1.81 (m, 4H), 1.65 (dt, J=15.7, 8.0 Hz, 6H), 1.36-1.15 (m, 4H). LC-MS (ESI) m/z (M+H)⁺: 817.42; calcd: 817.36; >95% purity.

Example 4

Synthesis of 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 51)

Step 1: Synthesis of 2-chloro-4-(8-(4-(4-(piperidin-4-yl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile

To a solution of 2-chloro-4-(8-(4-(piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile and tert-butyl 4-oxopiperidine-1-carboxylate in DCE was added NaBH(OAc)₃ (1.5 eq.), AcOH and TEA. The reaction mixture was stirred at r.t. for 6 h. All volatiles were removed and the residue was chromatographed on silica gel to afford the intermediate Boc protected compound. 2-Chloro-4-(8-(4-(4-(piperidin-4-yl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile was obtained by removing the Boc group using TFA in DCM. ESI-MS: 546.29.

Step 2: Synthesis of 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 51)

To a solution of 2-chloro-4-(8-(4-(4-(piperidin-4-yl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione in DMSO was added DIPEA (5 eq.). The reaction mixture was stirred at 100° C. for 12 h. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated, washed with water, and dried over Na₂SO₄. 2-Chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.43-7.37 (m, 3H), 7.32 (dd, J=8.7, 2.3 Hz, 1H), 7.02 (d, J=8.3 Hz, 2H), 6.73 (d, J=2.3 Hz, 1H), 6.58 (dd, J=8.9, 2.3 Hz, 1H), 5.12-5.07 (m, 2H), 4.25 (d, J=13.1 Hz, 2H), 3.63-3.38 (m, 8H), 3.29 (d, J=8.6 Hz, 6H), 3.03-2.84 (m, 4H), 2.61 (dt, J=13.8, 4.0 Hz, 2H), 2.20-2.13 (m, 2H), 2.05-1.99 (m, 1H), 1.92 (t, J=7.0 Hz, 2H), 1.68 (h, J=10.7, 7.2 Hz, 7H). LC-MS (ESI) m/z (M+H)⁺: 803.43; calcd: 803.34; >95% purity.

Example 5

Synthesis of 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 63)

Step 1: Synthesis of 4-(8-(4-(4-(azetidin-3-yl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)-2-chlorobenzonitrile

To a solution of 2-chloro-4-(8-(4-(piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile and tert-butyl 3-oxoazetidine-1-carboxylate in DCE was added NaBH(OAc)₃ (1.5 eq.), AcOH and TEA. The reaction mixture was stirred at r.t. for 6 h. All volatiles were removed and the residue was chromatographed on silica gel to afford the Boc protected compound. 4-(8-(4-(4-(Azetidin-3-yl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)-2-chlorobenzonitrile was obtained by removing the Boc group using TFA in DCM. ESI-MS: 518.26.

Step 2: Synthesis of 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 63)

To a solution of 4-(8-(4-(4-(azetidin-3-yl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)-2-chlorobenzonitrile and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione in DMSO was added DIPEA (5 eq.). The reaction mixture was stirred at 100° C. for 12 h. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated, washed with water, and dried over Na₂SO₄. 2-Chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. LC-MS (ESI) m/z (M+H)⁺: 815.45; calcd: 815.34; >95% purity.

Example 6

Synthesis of 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 72)

Step 1: Synthesis of 4-(8-(4-(4-(azetidin-3-ylmethyl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)-2-chlorobenzonitrile

To a solution of 2-chloro-4-(8-(4-(piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile and tert-butyl 3-(bromomethyl)azetidine-1-carboxylate in CH₃CN was added K₂CO₃ (2 eq.) and KI (20%). The reaction mixture was refluxed for 4 h. All volatiles were removed and the residue was chromatographed on silica gel to afford the Boc protected compound. 4-(8-(4-(4-(Azetidin-3-ylmethyl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)-2-chlorobenzonitrile was obtained by removing the Boc group using TFA in DCM. ESI-MS: 532.27.

Step 2: Synthesis of 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 72)

To a solution of 4-(8-(4-(4-(azetidin-3-ylmethyl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)-2-chlorobenzonitrile and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione in DMSO was added DIPEA (5 eq.). The reaction mixture was stirred at 100° C. for 12 h. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated, washed with water, and dried over Na₂SO₄. 2-Chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. LC-MS (ESI) m/z (M+H)⁺: 789.41; calcd: 789.33; >95% purity.

Example 7

Synthesis of 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 112)

Step 1: Synthesis of 2-chloro-4-(3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile

2-Chloro-4-fluorobenzonitrile and tert-butyl 3-methyl-2,8-diazaspiro[4.5]decane-8-carboxylate were dissolved in DMSO. To this solution was added DIPEA (5 eq.), and the reaction mixture was stirred at 100° C. for 4 h. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated, washed with water, and dried over Na₂SO₄. The Boc protected compound was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. 2-Chloro-4-(3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile was obtained by removing the Boc group using TFA in DCM. ESI-MS: 289.13.

Step 2: Synthesis of 4-(2-(3-chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoic acid

2-Chloro-4-(3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile and tert-butyl 4-bromobenzoate were dissolved in dioxane. To this solution was added Pd₂(dba)₃ (10%), xantphos (10%), and Cs₂CO₃ (3 eq.), and the reaction mixture was stirred at 100° C. for 6 h. The t-Bu ester compound was obtained by removing the solvent under vacuum and purified by flash column. 4-(2-(3-Chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoic acid was obtained by removing the t-Bu group using TFA in DCM. ESI-MS: 409.16.

Step 3: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(piperazin-1-yl)azetidin-1-yl)isoindoline-1,3-dione

tert-Butyl 4-(azetidin-3-yl)piperazine-1-carboxylate and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione were dissolved in DMSO. To this solution was added DIPEA (5 eq.), and the reaction mixture was stirred at 100° C. for 4 h. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated, washed with water, and dried over Na₂SO₄. The Boc protected compound was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. 2-(2,6-Dioxopiperidin-3-yl)-5-(3-(piperazin-1-yl)azetidin-1-yl)isoindoline-1,3-dione was obtained by removing the Boc group using TFA in DCM. ESI-MS: 397.18.

Step 4: Synthesis of 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 112)

4-(2-(3-Chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoic acid and 2-(2,6-dioxopiperidin-3-yl)-5-(3-(piperazin-1-yl)azetidin-1-yl)isoindoline-1,3-dione were dissolved in DMF. To this solution was added DIPEA (5 eq.) and HATU (1.2 eq.), the reaction mixture was stirred at r.t. for 1 h. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated, washed with water, dried over Na₂SO₄, and purified by flash column chromatography on silica gel to give 2-Chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.37 (d, J=8.3 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 6.92 (s, 1H), 6.84-6.74 (m, 2H), 6.66 (d, J=8.9 Hz, 1H), 5.08 (dd, J=12.8, 5.4 Hz, 1H), 4.39-4.17 (m, 8H), 4.04 (h, J=6.7 Hz, 2H), 3.86-3.64 (m, 4H), 3.44-3.28 (m, 5H), 2.89 (ddd, J=19.0, 14.1, 5.7 Hz, 2H), 2.59 (dd, J=19.8, 5.9 Hz, 2H), 2.25 (dd, J=12.9, 7.7 Hz, 1H), 2.02 (dd, J=12.8, 6.5 Hz, 1H), 1.72 (h, J=5.7 Hz, 2H), 1.58-1.45 (m, 3H), 1.21 (d, J=6.0 Hz, 3H). LC-MS (ESI) m/z (M+H)⁺: 789.40; calcd: 789.33; >95% purity.

Example 8

Synthesis of 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 114)

Step 1: Synthesis of 2-chloro-4-(3-methyl-8-(4-(piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile

4-(2-(3-Chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoic acid and tert-butyl piperazine-1-carboxylate were dissolved in DMF. To this solution was added DIPEA (5 eq.) and HATU (1.2 eq.), and the reaction mixture was stirred at r.t. for 1 h. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated, washed with water, and dried over Na₂SO₄. The Boc protected compound was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. 2-Chloro-4-(3-methyl-8-(4-(piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile was obtained by removing the Boc group using TFA in DCM. ESI-MS: 477.23.

Step 2: Synthesis of 4-(8-(4-(4-(azetidin-3-ylmethyl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)-2-chlorobenzonitrile

To a solution of 2-chloro-4-(3-methyl-8-(4-(piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile and tert-butyl 3-(bromomethyl)azetidine-1-carboxylate in CH₃CN was added K₂CO₃ (2 eq.) and KI (20%). The reaction mixture was refluxed for 4 h. All volatiles were removed and the residue was chromatographed on silica gel to afford the Boc protected compound. 4-(8-(4-(4-(Azetidin-3-ylmethyl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)-2-chlorobenzonitrile was obtained by removing the Boc group using TFA in DCM. ESI-MS: 546.29.

Step 3: Synthesis of 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 114)

To a solution of 4-(8-(4-(4-(azetidin-3-ylmethyl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)-2-chlorobenzonitrile and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione in DMSO was added DIPEA (5 eq.). The reaction mixture was stirred at 100° C. for 12 h. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated, washed with water, and dried over Na₂SO₄. 2-Chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.39 (d, J=8.5 Hz, 2H), 7.04 (d, J=8.4 Hz, 2H), 6.80 (d, J=2.1 Hz, 2H), 6.72-6.60 (m, 2H), 5.07 (dd, J=12.9, 5.4 Hz, 1H), 4.24 (t, J=8.2 Hz, 2H), 4.04 (q, J=6.6 Hz, 1H), 3.85 (dd, J=8.6, 5.6 Hz, 2H), 3.68-3.05 (m, 16H), 2.89 (ddd, J=17.4, 13.9, 5.5 Hz, 1H), 2.64-2.54 (m, 2H), 2.25 (dd, J=12.8, 7.7 Hz, 1H), 2.10-1.98 (m, 1H), 1.76 (td, J=8.2, 7.0, 3.9 Hz, 2H), 1.63-1.46 (m, 3H), 1.37-1.24 (m, 1H), 1.21 (d, J=6.0 Hz, 3H). LC-MS (ESI) m/z (M+H)⁺: 803.42; calcd: 803.34; >95% purity.

Example 9

Synthesis of 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-1-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 120)

Step 1: Synthesis of 2-chloro-4-(1-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile

2-Chloro-4-fluorobenzonitrile and tert-butyl 1-methyl-2,8-diazaspiro[4.5]decane-8-carboxylate were dissolved in DMSO. To this solution was added DIPEA (5 eq.), and the reaction mixture was stirred at 100° C. for 4 h. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated, washed with water, and dried over Na₂SO₄. The Boc protected compound was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. 2-Chloro-4-(1-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile was obtained by removing the Boc group using TFA in DCM. ESI-MS: 289.13.

Step 2: Synthesis of 4-(2-(3-chloro-4-cyanophenyl)-1-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoic acid

2-Chloro-4-(1-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile and tert-butyl 4-bromobenzoate were dissolved in dioxane. To this solution was added Pd₂(dba)₃ (10%), xantphos (10%), and Cs₂CO₃ (3 eq.), and the reaction mixture was stirred at 100° C. for 6 h. The t-Bu ester compound was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. 4-(2-(3-Chloro-4-cyanophenyl)-1-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoic acid was obtained by removing the t-Bu group using TFA in DCM. ESI-MS: 409.16.

Step 3: Synthesis of 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-1-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 120)

4-(2-(3-Chloro-4-cyanophenyl)-1-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoic acid and 2-(2,6-dioxopiperidin-3-yl)-5-(3-(piperazin-1-yl)azetidin-1-yl)isoindoline-1,3-dione were dissolved in DMF. To this solution was added DIPEA (5 eq.) and HATU (1.2 eq.), and the reaction mixture was stirred at r.t. for 1 h. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated, washed with water, and dried over Na₂SO₄, and purified by flash column chromatography on silica gel to give 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-1-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.57 (d, J=8.9 Hz, 1H), 7.43 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.5 Hz, 2H), 6.92 (d, J=2.0 Hz, 1H), 6.79-6.73 (m, 2H), 6.60 (dd, J=9.0, 2.2 Hz, 1H), 5.09 (dd, J=12.8, 5.5 Hz, 1H), 4.35 (dt, J=21.2, 7.6 Hz, 5H), 4.00-3.69 (m, 4H), 3.42 (dt, J=20.2, 10.0 Hz, 10H), 2.95-2.85 (m, 1H), 2.58 (ddd, J=22.8, 13.1, 4.2 Hz, 2H), 2.08-1.91 (m, 3H), 1.79-1.64 (m, 2H), 1.54 (q, J=8.5, 7.2 Hz, 2H), 1.26 (td, J=7.5, 7.0, 4.4 Hz, 1H), 1.04 (d, J=6.2 Hz, 3H). LC-MS (ESI) m/z (M+H)⁺: 789.43; calcd: 789.33; >95% purity.

Example 10

Synthesis of 2-chloro-4-((3S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 293)

Step 1: Synthesis of (S)-2-chloro-4-(3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile

2-Chloro-4-fluorobenzonitrile and tert-butyl (S)-3-methyl-2,8-diazaspiro[4.5]decane-8-carboxylate were dissolved in DMSO. To this solution was added DIPEA (5 eq.), and the reaction mixture was stirred at 100° C. for 4 h. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated, washed with water, and dried over Na₂SO₄. The Boc protected compound was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. (S)-2-Chloro-4-(3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile was obtained by removing the Boc group using TFA in DCM. ESI-MS: 289.13.

Step 2: Synthesis of (S)-4-(2-(3-chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoic acid

(S)-2-Chloro-4-(3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile and tert-butyl 4-bromobenzoate were dissolved in dioxane. To this solution was added Pd₂(dba)₃ (10%), xantphos (10%), and Cs₂CO₃ (3 eq.), and the reaction mixture was stirred at 100° C. for 6 h. The t-Bu ester compound was obtained by removing the solvent under vacuum and purified by flash column. (S)-4-(2-(3-Chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoic acid was obtained by removing the t-Bu group using TFA in DCM. ESI-MS: 409.16.

Step 3: Synthesis of 2-chloro-4-((3S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 293)

(S)-4-(2-(3-Chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoic acid and 2-(2,6-dioxopiperidin-3-yl)-5-(3-(piperazin-1-yl)azetidin-1-yl)isoindoline-1,3-dione were dissolved in DMF. To this solution was added DIPEA (5 eq.) and HATU (1.2 eq.), and the reaction mixture was stirred at r.t. for 1 h. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated, washed with water, dried over Na₂SO₄, and purified by flash column chromatography on silica gel to give 2-chloro-4-((3S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 789.42; calcd: 789.33; >95% purity.

Example 11

Synthesis of 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)-3-methylbenzonitrile (Cpd. No. 109)

Step 1: Synthesis of 2-chloro-3-methyl-4-(2,8-diazaspiro[4.5]decan-2-yl)benzonitrile

2-Chloro-4-iodo-3-methylbenzonitrile and tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate were dissolved in dioxane. To this solution was added Pd₂(dba)₃ (10%), xantphos (10%), and Cs₂CO₃ (3 eq.), and the reaction mixture was stirred at 100° C. for 6 h. The Boc protected compound was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. 2-Chloro-3-methyl-4-(2,8-diazaspiro[4.5]decan-2-yl)benzonitrile was obtained by removing the Boc group using TFA in DCM. ESI-MS: 289.13.

Step 2: Synthesis of 4-(2-(3-chloro-4-cyano-2-methylphenyl)-2,8-diazaspiro[4.5]decan-8-yl)benzoic acid

2-Chloro-3-methyl-4-(2,8-diazaspiro[4.5]decan-2-yl)benzonitrile and tert-butyl 4-bromobenzoate were dissolved in dioxane. To this solution was added Pd₂(dba)₃ (10%), xantphos (10%), and Cs₂CO₃ (3 eq.), and the reaction mixture was stirred at 100° C. for 6 h. The t-Bu ester compound was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. 4-(2-(3-Chloro-4-cyano-2-methylphenyl)-2,8-diazaspiro[4.5]decan-8-yl)benzoic acid was obtained by removing the t-Bu group using TFA in DCM. ESI-MS: 409.16.

Step 3: Synthesis of 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)-3-methylbenzonitrile (Cpd. No. 109)

4-(2-(3-Chloro-4-cyano-2-methylphenyl)-2,8-diazaspiro[4.5]decan-8-yl)benzoic acid and 2-(2,6-dioxopiperidin-3-yl)-5-(3-(piperazin-1-yl)azetidin-1-yl)isoindoline-1,3-dione were dissolved in DMF. To this solution was added DIPEA (5 eq.) and HATU (1.2 eq.), and the reaction mixture was stirred at r.t. for 1 h. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated, washed with water, dried over Na₂SO₄, and purified by flash column chromatography on silica gel to give 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)-3-methylbenzonitrile. ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.54 (d, J=8.7 Hz, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.3 Hz, 2H), 6.95-6.72 (m, 4H), 5.09 (dd, J=12.8, 5.4 Hz, 1H), 4.34 (dd, J=21.4, 8.7 Hz, 6H), 3.80 (s, 3H), 3.52-3.32 (m, 10H), 3.00-2.81 (m, 2H), 2.56 (dd, J=31.2, 14.5 Hz, 3H), 2.06-1.60 (m, 9H). LC-MS (ESI) m/z (M+H)⁺: 789.43; calcd: 789.33; >95% purity.

Example 12

Synthesis of 2-chloro-4-((3S)-8-(4-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 307)

Steps 1 and 2

Compound 1 (1.5 eq) and 2 (1 eq) were dissolved in DMF, and Cs₂CO₃ (3.0 eq) was added. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was cooled to rt and partitioned between EtOAc and H₂O. The organic phase was separated, washed with water, dried over Na₂SO₄, and purified by flash column chromatography on silica gel (Combiflash, hexane and EtOAc). UPLC-MS:, 6.3 min, 390.31. The product was dissolved in 10×DCM, and TFA (2×) was added and stirring at rt for 2 h. The solvent was distilled and dried on the lyophilizer overnight to give compound 4.

Steps 3 and 4

Compound 4 (1.0 eq) and compound 5 (2.0 eq) were dissolved in DMF, and K₂CO₃ (3.0 eq) was added. The reaction mixture was stirred at 120° C. overnight. The reaction mixture was cooled to rt and partitioned between EtOAc and H₂O. The organic phase was separated, washed with water, dried over Na₂SO₄, and purified by flash column chromatography on silica gel (Combiflash, Hexane and EtOAc). The product was dissolved in 10×DCM, and TFA (3×) was added and stirring at rt for 2 h. The solvent was distilled and dried on the lyophilizer overnight to give compound 7.

Step 5

Compound 7 (1.0 eq.) was dissolved in DCM (5×). DIPEA (2.0 eq) was added followed by HATU (1.3 eq). In a separate flask, compound 8 (1.0 eq) was dissolved in DMF (5×) and DIPEA (2.0 eq) was added slowly. The basified compound 8 solution was poured into the compound 7 solution, and the reaction mixture was allowed to stir for 0.5 h. The reaction mixture was partitioned between EtOAc and H₂O. The organic phase was separated, washed with water, dried over Na₂SO₄, and purified by flash column chromatography on silica gel (Combiflash, hexane and EtOAc).

Step 6

Compound 9 (2.0 eq) was dissolved in DCE (10×), and compound 10 (1.0 eq), and AcOH (3 eq.) were added. The mixture was stirred at rt for 2 h. Molecular sieves (4 angstrom) (3×) were added, and the mixture was stirred for 12 h. NaB(OAc)₃H (3.0 eq) was added, and the mixture was stirred at rt overnight to give Cpd. No. 307. UPLC-MS: 3.6 min, 774.23. HPLC 35%.

Example 13

Synthesis of 2-chloro-4-((3S)-8-(4-(4-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 311)

The synthesis of Cpd. No. 311 was similar to the synthesis of Cpd. No. 307 as shown in EXAMPLE 12, except compound 13 was converted to compound 14 as follows. Compound 13 (1.0 eq) was dissolved in DCE (10×), Dess Martin reagent (1.4 eq.) was added. The above mixture was stirred at rt for 2 h. The reaction mixture was placed on a Combiflash and eluted with DCM/MeOH to give Cpd. No. 311. UPLC-MS: 3.7 min, 788.32. HPLC 36%.

Example 14

Synthesis of 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 201)

Steps 1 and 2

Compound 1 (1.5 eq) and 2 (1 eq) were dissolved in DMF, and Cs₂CO₃ (3.0 eq) was added. The reaction mixture was stirred at 90° C. overnight. The reaction mixture was cooled to rt and partitioned between EtOAc and H₂O. The organic layer was dried and concentrated and purified by flash column chromatography on silica gel (Combiflash, Hexanes and EtOAc). The product was dissolved in 10×DCM, and TFA (2×) was added with stirring at rt for 2 h. The solvent was removed and dried on the lyophilizer overnight to give compound 4. Compound 2 was synthesized following the procedure described in Journal of Organic Chemistry, 81(9):3509-3519 (2016).

Steps 3 and 4

Compound 4 (1.0 eq.), K₂CO₃ (4.0 eq), and compound 5 (1.0 eq) were dissolved in DMF (5×). The mixture was stirred at 120˜130° C. overnight. The reaction was partitioned between EtOAc and H₂O. The organic layer was dried and concentrated and purified by flash column chromatography on silica gel (Combiflash, Hexanes and EtOAc). The product was dissolved in 10×DCM, and TFA (10×) was added with stirring at rt for 2 h. The solvent was distilled and dried on the lyophilizer overnight to give compound 7.

Steps 5 and 6

Compound 7 (1.0 eq.) was dissolved in DCM (5×). DIPEA (2.0 eq) was added followed by HATU (1.3 eq). After 10 minutes, compound 8a (1.3 eq) was added, and the reaction was allowed to stir for 0.5 h. The reaction was partitioned between EtOAc and H₂O. The organic layer was dried and concentrated and purified by flash column chromatography on silica gel (Combiflash, Hexanes and EtOAc). The product was dissolved in 10×DCM, and TFA (2×) was added with stirring at rt for 2 h. The solvent was distilled and dried on the lyophilizer overnight to give compound 9.

Steps 7 and 8

Compound 9 (1.0 eq) was dissolved in DCE (10×), and compound 10 (1.8 eq), and AcOH (3 eq.) were added. The above mixture was stirred at rt for 2 h. NaB(OAc)₃H (3.0 eq) was added, and the mixture was stirred at rt overnight. After UPLC-MS validating full conversion of compound 9, the reaction mixture was directly placed on cartridge with Celite® at the bottom, and was eluted with DCM and MeOH using Combiflash. The product was dissolved in 10×DCM, and TFA (2×) was added with stirring at rt for 2 h. The solvent was distilled and dried on the lyophilizer overnight to give compound 13.

Step 7

Compound 13 (1.0 eq)) was dissolved in DMF (4×), and compound 14 (2.0 eq) and DIPEA (4 eq.) were added. The above mixture was stirred at 90° C. overnight. LC-MS indicated compound 10 was fully consumed. Cpd. No. 201 was purified by preparative HPLC. UPLC-MS: LC-MS, 4.3 min, 831.42; HPLC 41% ACN in water. Compound 14 was synthesized in one step reaction following the procedure described in J Med Chem 61(2):462-481 (2018).

Example 15

Synthesis of 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 200)

The synthesis of Cpd. No. 200 was similar to the synthesis of Cpd. No. 201 as shown in EXAMPLE 14, except the reaction of compound 9 with compound 16 as shown in the scheme above.

Step 9 to 17

Compound 9 (1.0 eq) was dissolved in DCE (10×), and compound 10 (1.8 eq), and AcOH (3 eq.) were added. The above mixture was stirred at rt for 2 h. NaB(OAc)₃H (3.0 eq) was added and the mixture was stirred at rt for 4 h. After UPLC-MS validating full conversion of compound 9, the reaction was purified by combiflash to give Cpd. No. 200: UPLC-MS: 4.2 min, 817.30; HPLC 42% ACN in water.

Example 16

Synthesis of 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-1-carbonyl)phenyl)-1-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 203)

The synthesis of Cpd. No. 203 was similar to the synthesis of Cpd. No. 201 as shown in EXAMPLE 14.

Example 17

Synthesis of 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)phenyl)-1-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 202)

The synthesis of Cpd. No. 202 is similar to the synthesis of Cpd. No. 200 as shown in EXAMPLE 16.

Example 18

Synthesis of tert-butyl (S)-1-methyl-2,8-diazaspiro[4.5]decane-8-carboxylate (S-2) and tert-butyl (R)-1-methyl-2,8-diazaspiro[4.5]decane-8-carboxylate (R-2)

Method 1—Synthesis of Racemic (Rac)-2

Step 1

Compound a (1.0 eq) was dissolved in anhydrous THF in a well dried flask at ° C. NaH (1.2 eq) was added. After 0.5 h, the reaction was warmed to rt and stirred for 2˜3 h. The reaction was cooled to 0° C., and TMSCl (1.15 eq) was dropped slowly. After 0.5 h, the reaction was warmed to rt and stirred for 3˜4 h. The reaction was cooled to −78° C., and MeLi.LiBr solution (1.1 eq) was added dropwise. After 5 h, the reaction was quenched with H₂O. DCM was added and organic layer was washed and dried. Combiflash: DCM and MeOH. MS: a: 255.23; b: 253.31.

Step 2

Compound b (1.0 eq) was dissolved in THF (10×), and NaBH₄ (1.5 eq) was added. After 2 h, the reaction was quenched by water. DCM (20×) was added and the organic layer was washed with NH₄OH (conc) and water, and purified by Combiflash: 100% EtOAc to DCM and MeOH.

Method 2—Synthesis of Racemic (Rac)-2

The procedure was reported in J. Org. Chem 81:3509-3519 (2016)

Chiral separation of rac-2 (R, S will be determined by further analysis):

Resolution:

Step a

Rac-2 (1.0 eq) was dissolved in EtOH (5×) and (L-DTTA (1.0 eq) was dissolved in EtOH (5×). The solutions were combined in an ice-bath slowly with stirring. The mixture was stirred at rt overnight. The precipitate was filtered and dried. The filtrate was collected to be used in step d.

Step b

The solid from step a was dissolved in EtOH (2% water was added) at reflux. The solvent was distilled to a point, at which suspension start to precipitate. The distillation was stopped, and the solution was heated to reflux. EtOH was added slowly until the suspension disappeared. The temperature was slowly decreased, and the solution was stirred at rt for 1 day and 0° C. for 1 h. The suspension was filtered and dried. The filtrate was collected for step d.

Step c

The solid for step b was basified by NaOH and extracted with DCM. The organic layer was washed with water and dried to give S-2.

Step d

The filtrates from step a and step b were combined, and distilled to get a semisolid, which was then basified by NaOH and extracted with DCM and concentrated and dried. The resulting solid was resolved with D-DTTA following the step a, step b and step c to provide R-2.

The yield for S-2 was about 29% and R-2 was 21%.

Example 19

Synthesis of tert-butyl (S)-3-methyl-2,8-diazaspiro[4.5]decane-8-carboxylate (S-3) and tert-butyl (R)-3-methyl-2,8-diazaspiro[4.5]decane-8-carboxylate (R-3)

The same resolution method described above for S-2 and R-2 can be used to prepare S-3 and R-3. S-3 and R-3 can also be prepared using the following chiral synthesis.

Example 20

Synthesis of 2-chloro-4-(8-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 151)

Step 1

To a suspension of 2-chloro-4-fluorobenzonitrile (1.0 g, 6.5 mmol) in DMF (3 mL) was added tert-butyl 3-methyl-313-2,8-diazaspiro[4.5]decane-8-carboxylate (1.65 g, 6.5 mmol, 1 eq), and the reaction mixture was heated to 900 for 10 h. The reaction mixture was cooled and poured into the mixture of ice-water. The reaction mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated. The crude was purified on silica gel (Hexane/EtOAc 2:1) to give tert-butyl 2-(3-chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decane-8-carboxylate as yellow oil. Then 4.0 M Hydrogen chloride solution in dioxane (4 mL) was added and the mixture was stirred for 2 h. The volatiles were evaporated under vacuum to afford Compound 1 as a white solid (1.5 g, 83%).

Step 2

To a Schlenk tube was charged with Compound 1 (1.5 g, 5.4 mmol), tert-butyl 4-iodobenzoate (2.1 g, 7.0 mmol), Pd₂(dba)₃ (64 mg, 0.07 mmol), Xantphos (81 mg, 0.14 mmol), Cs₂CO₃ (3.9 g, 12 mmol), toluene (5 mL) under N₂. The tube was sealed and heated at 100° C. oil bath for 12 h. The reaction mixture was extracted with EtOAc and the organic layer was washed with brine, dried and concentrated. The residue was purified on silica gel to afford Compound 2 as a dark oil (1.4 g, 56%). ESI: M+H 466.40.

Step 3

Compound 2 was added to 4 ml of TFA. The Mixture was stirred at room temperature overnight. The volatiles were evaporated under vacuum to afford Compound 3 as a yellow oil (1.1 g, 92%). ESI: M+H 410.32.

Step 4

To a solution of Compound 4 (1000 mg, 3.1 mmol)) in DCE (10 mL) was added NaBH(OAc)₃ (1.7 g, 8 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (1.3 g, 6 mmol). The reaction mixture was stirred for 4 h prior to being quenched with Na₂CO₃ solution (2 M). The reaction mixture was extracted with EtOAc, washed with saturated NaHCO₃ solution. The residue was purified by chromatography on silica gel (DCM and methanol) to give tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate. Then 4.0 M hydrogen chloride solution in dioxane (4 mL) was added and the mixture was stirred for 2 h. The volatiles were evaporated under vacuum to afford Compound 5 as a dark solid (935 mg, 71%). ESI: M+H 425.44.

Step 5

To a solution of Compound 3 (100 mg, 0.24 mmol)) in DMF (4 mL) was added Compound 5 (127 mg, 0.30 mmol), DIPEA (78 mg, 0.6 mmol) and HATU (152 mg, 0.4 mmol). The reaction mixture was stirred for 12 h. The reaction mixture was extracted with EtOAc and the organic layer was washed with brine, dried and concentrated. The residue was purified on HPLC to afford the title compound (113 mg, 58%). ¹H NMR (400 MHz, MeOD) δ 7.75 (d, J=9.6 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 7.48-7.42 (m, 2H), 7.28-7.18 (m, 5H), 6.83-6.80 (m, 2H), 6.72-6.68 (m, 2H), 5.19-5.10 (m, 3H), 4.49-4.44 (m, 4H), 3.60-3.34 (m, 12H), 3.24-2.80 (m, 7H), 2.80-2.14 (m, 6H), 1.98-1.60 (m, 5H), ESI-MS: 817.42.

Example 21

Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,4-g]isoquinoline-1,3(2H)-dione (Compound 9)

Step 1: Synthesis of dimethyl isoquinoline-6,7-dicarboxylate (Compound 3)

A mixture of 3-bromopyridine-4-carbaldehyde (1, 0.093 g, 0.5 mmol), dimethyl itaconate (2, 0.079 g, 0.5 mmol), Pd(OAc)₂ (0.0056 g, 0.025 mmol), PPh₃ (0.013 g, 0.05 mmol) and NaOAc (0.123 g, 1.5 mmol) in dioxane (10 mL) was placed in a 50 mL pressure vessel. After the system was flushed with argon, the reaction mixture was allowed to react at 150° C. for 24 h, and then the reaction mixture was cooled to room temperature. The reaction mixture was filtered through Celite® to eliminate inorganic salts and washed by ethyl acetate. Removal of the solvent left a crude mixture which was purified by flash chromatography on silica gel (ethyl acetate-hexane) to give dimethyl isoquinoline-6,7-dicarboxylate (3, 0.082 g, 67%).

Step 2: Synthesis of 2-(tert-butyl) 6,7-dimethyl 3,4-dihydroisoquinoline-2,6,7(1H)-tricarboxylate (Compound 4)

Compound 3 (279.6 mg, 1.14 mmol) was dissolved in mixture solvent of methanol (4 mL) and acetic acid (0.2 mL). PtO₂ (30 mg) was added, and the reaction mixture was stirred under hydrogen at room temperature for 4 h. The reaction mixture was filtered through Celite®. The filtrate was collected and concentrated under reduced pressure to give the crude product.

The crude product was dissolved in mixture of THF (4 mL) and water (1 mL), and Na₂CO₃ (500 mg) and Boc₂O (500 mg, 2.28 mmol) were added to the mixture. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to remove the THF, and the crude mixture dissolved in water (5 mL) and ethyl acetate (10 mL). The organic layer was separated, washed with water and brine, dried (MgSO₄), concentrated under reduced pressure, and purified by flash chromatography on silica gel (ethyl acetate-hexane) to give compound 4 (130 mg).

Step 3: Synthesis of 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-6,7-dicarboxylic acid (Compound 5)

3N NaOH (0.37 mL, 1.12 mmol) was added to a solution of compound 4 (130 mg, 0.37 mmol) in EtOH (3.7 mL) and the resulting mixture heated at 80° C. for 2 h. The reaction was concentrated under reduced pressure and the crude mixture dissolved in water (5 mL) and ethyl acetate (10 mL) and then acidified using 1N HCl to pH ˜4 in an ice bath. The organic layer was separated and the aqueous layer was extracted with ethyl acetate two more times. The combined the organic layers were washed with brine (10 mL), dried (MgSO₄), and concentrated under reduced pressure. The crude product was used in the next step without further purification.

Step 4: Synthesis of tert-butyl 1,3-dioxo-1,5,7,8-tetrahydrofuro[3,4-g]isoquinoline-6(3H)-carboxylate (Compound 6)

Compound 5 (the crude product from step 3) was dissolved in acetic anhydride (2 mL) and the reaction mixture was stirred at 100° C. for 3 h. The reaction mixture was cooled to room temperature, and 10 mL ethyl acetate was added. The reaction mixture was washed with water and brine, dried (MgSO₄), concentrated under reduced pressure, and purified by flash chromatography on silica gel (ethyl acetate-hexane) to give compound 6 (123.1 mg).

Step 5: Synthesis of tert-butyl 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1,2,3,5,7,8-hexahydro-6H-pyrrolo[3,4-g]isoquinoline-6-carboxylate (Cpd. No. 249)

Compound 6 (123.1 mg, 0.41 mmol), compound 7 (73.5 mg, 0.45 mmol) and Et₃N (0.17 mL, 1.23 mmol) were added to toluene (5 mL). The reaction mixture was stirred at 80° C. for 3 h and then cooled to room temperature. The reaction was concentrated under reduced pressure and the crude mixture dissolved in water (5 mL) and ethyl acetate (10 mL). The organic layer was separated, washed with water and brine, dried (MgSO₄), concentrated under reduced pressure, and purified by flash chromatography (ethyl acetate-hexane) to give Compound 8.

Step 6: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,4-g]isoquinoline-1,3(2H)-dione (Compound 9)

Compound 8 (102.1 mg, 0.24 mmol) was added to 1 mL HCl (4M in 1,4-dioxane), and the mixture reaction mixture was stirred at room temperature for 2 h. The 1,4-dioxane was removed under reduced pressure to give compound 9 as the HCl salt.

Example 22

Synthesis of 2-(2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione (Compound 18)

Step 1: Synthesis of tert-butyl di(prop-2-yn-1-yl)carbamate (Compound 12)

A solution of N-(tert-butyloxy)carbonyl propargylamine (compound 10; 33.36 g, 215 mmol) in 50 mL of DMF was treated portionwise (4 times) with 60% NaH (10.4 g) at 0° C. After stirring for 30 min at 25° C., 39 mL of an 80% solution of propargyl bromide (compound 11) in toluene was added. The reaction mixture was stirred for an additional 5 h at 25° C., and then quenched with the addition of ice-water. The mixture was extracted with Et₂O (3×200 mL), and the combined extracts were washed with saturated aqueous NaCl, dried (Na₂SO₄), concentrated in vacuo, and purified by flash chromatography on silica gel (ethyl acetate-hexane) to give compound 12.

Step 2: Synthesis of 2-(tert-butyl) 5,6-dimethyl isoindoline-2,5,6-tricarboxylate (Compound 14)

A solution of compound 12 (10.4 g, 53.9 mmol) and dimethyl acetylenedicarboxylate (compound 13, 30.7 g, 216 mmol) in 110 mL of absolute EtOH was degassed by bubbling N₂ through the solution for 10 min. To this solution was added 1.0 g (0.02 equiv) of Wilkinson's catalyst [(Ph₃P)₃RhCl] at 25° C. After being warmed at reflux for 18 h, the reaction mixture was cooled to 25° C. and concentrated in vacuo. The resulting brown residue was diluted in 200 mL of Et₂O, and the precipitate was removed by filtration over Celite®. The filtrate was concentrated and the crude product purified by column chromatography on silica gel (20% EtOAc/hexane) to give 4.60 g (26%) of compound 14.

The remaining steps for synthesizing Compound 18 (as the HCl salt) are essentially the same as Steps 3-6 described above in EXAMPLE 21.

Example 23

Synthesis of 2-chloro-4-(8-(4-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)-3-methylbenzonitrile (Cpd. No. 355)

Compound 1 (1.0 eq) was dissolved in DCE (10×), and compound 2 (2.0 eq) and AcOH (3 eq.) were added. The mixture was stirred at rt for 2 h. Molecular sieves (4 angstrom) (3×) were added, and the mixture was stirred for 12 h. NaB(OAc)₃H (3.0 eq) was added, and the mixture was stirred at rt overnight. The reaction was concentrated and purified on a Combiflash chromatography system using MeOH/DCM as the eluent to give compound 3 in 70% yield. The product was dissolved in 10×DCM, and TFA (2×) was added. The reaction mixture was stirred at rt for 2 h. The solvent was distilled and dried on a lyophilizer overnight to give compound 4.

Compound 5 (1.5 eq) and compound 6 (1 eq) were dissolved in DMF, and Cs₂CO₃ (3.0 eq), Pd₂(dba)₃ (0.05×), xphose (0.05×) were added. The reaction mixture was stirred overnight at 90° C. The reaction mixture was cooled to rt and partitioned between EtOAc and H₂O. The organic phase was separated, washed with water, dried over Na₂SO₄, and purified by flash column chromatography on silica gel (Combiflash using hexane and EtOAc at the eluent). The product was dissolved in 10×DCM, and TFA (2×) was added. The reaction mixture was stirred at rt for 2 h. The solvent was distilled and dried on a lyophilizer overnight to give compound 8.

Compound 8 (1.0 eq) and compound 9 (2.0 eq) were dissolved in DMF, and KHCO₃ (3.0 eq) was added. The reaction mixture was stirred at 120° C. for 2 h. The reaction mixture was cooled to rt and partitioned between EtOAc and H₂O. The organic phase was separated, washed with water, dried over Na₂SO₄, and purified by flash column chromatography on silica gel (Combiflash using Hexane and EtOAc as the eluent). The product was dissolved in 10×DCM, and TFA (5×) was added. The reaction mixture was stirred at rt for 2 h. The solvent was distilled and dried on a lyophilizer overnight to give compound 11.

Compound 11 (1.0 eq.) was dissolved in DCM (5×). DIPEA (2.0 eq) was added followed by HATU (1.3 eq). In a separate flask, compound 4 (1.0 eq) was dissolved in DMF (5×) and DIPEA (2.0 eq) was added slowly. The compound 4 solution was poured into the compound 11 solution, and the reaction mixture was allowed to stir for 0.5 h to give Cpd. No. 355 in 39% yield. UPLC-MS: 3.9 min, 788.43.

Example 24

Synthesis of 2-chloro-4-((3S)-8-(4-(4-((6-(2,6-dioxopiperidin-3-yl)-5-oxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 364)

Compound 1 (1.0 eq) was dissolved in DCE (10×), and compound 2 (2.0 eq) and AcOH (3 eq.) were added. The mixture was stirred at rt for 2 h. Molecular sieves (4 angstrom) (3×) were added, and the mixture was stirred for 12 h. NaB(OAc)₃H (3.0 eq) was added, and the mixture was stirred at rt overnight. The reaction was concentrated and purified on a Combiflash chromatography system using MeOH/DCM as the eluent to give compound 3 in 90% yield. Compound 3 was dissolved in 10×DCM, and TFA (2×) was added. The reaction mixture was stirred at rt for 2 h. The solvent was distilled and the product was dried on a lyophilizer overnight to give compound 4.

Compound 5 (1.0 eq.) was dissolved in DCM (5×). DIPEA (2.0 eq) was added followed by HATU (1.3 eq). In a separate flask, compound 4 (1.0 eq) was dissolved in DMF (5×) and DIPEA (2.0 eq) was added slowly. The compound 4 solution was poured into the compound 5 solution, and the reaction mixture was allowed to stir for 0.5 h to give Cpd. No. 364 in 37% yield. UPLC-MS: 3.6 min, 788.36.

Example 25

Synthesis of 2-chloro-4-((3S)-8-(4-(4-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)-4-fluoropiperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 365)

Cpd. No. 365 was synthesized following the procedure of EXAMPLE 24 with the starting chemicals showed in the above scheme.

Example 26

Synthesis of 2-chloro-4-((3S)-8-(4-(4-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)-4-methoxypiperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 366)

Cpd. No. 366 was synthesized following the procedure of EXAMPLE 24 with the starting chemicals showed in the above scheme.

Example 27

Synthesis of 2-chloro-4-((3S)-8-(4-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)piperidine-1-carbonyl)phenyl)-3-ethyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 367)

Compound 4 was prepared using methods described in EXAMPLE 19.

Compound 5 (1.5 eq) and 4 (1 eq) were dissolved in DMF, and Cs₂CO₃ (3.0 eq) was added. The reaction mixture was stirred overnight at 90° C. The reaction mixture was cooled to rt and partitioned between EtOAc and H₂O. The organic phase was separated, washed with water, dried over Na₂SO₄, and purified by flash column chromatography on silica gel (Combiflash using hexane and EtOAc as the eluent). The product was dissolved in 10×DCM, and TFA (2×) was added and stirring at rt for 2 h. The product was dissolved in 10×DCM, and TFA (5×) was added. The reaction mixture was stirred at rt for 2 h. The solvent was distilled and dried on a lyophilizer overnight to give compound 7.

Compound 8 (1.5 eq) and compound 7 (1 eq) were dissolved in DMF, and Cs₂CO₃ (3.0 eq), Pd₂(dba)₃ (0.05×), and xphose (0.05×) were added. The reaction mixture was stirred overnight at 90° C. The reaction mixture was cooled to rt and partitioned between EtOAc and H₂O. The organic phase was separated, washed with water, dried over Na₂SO₄, and purified by flash column chromatography on silica gel (Combiflash using hexane and EtOAc as the eluent). The product was dissolved in 10×DCM, and TFA (2×) was added. The reaction mixture was stirred at rt for 2 h. The solvent was distilled and dried on a lyophilizer overnight to give compound 10.

Compound 10 (1.0 eq.) was dissolved in DCM (5×). DIPEA (2.0 eq) was added followed by HATU (1.3 eq). In a separate flask, compound 11 (1.0 eq) was dissolved in DMF (5×) and DIPEA (2.0 eq) was added slowly. The compound 11 solution was poured into the compound 10 solution, and the reaction mixture was allowed to stir for 0.5 h to give Cpd. No. 367 in 38% yield. UPLC-MS: 3.7 min, 788.42.

Example 28

Synthesis of 2-chloro-4-((1S)-8-(4-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)piperidine-1-carbonyl)phenyl)-1-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 370)

Cpd. No. 370 was prepared following the procedure of EXAMPLE 27 with the starting chemicals showed in the above scheme.

Example 29

Synthesis of 2-chloro-4-((3S)-8-(4-(3-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)azetidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 371)

Cpd. No. 371 was prepared following the procedure of EXAMPLE 24 with the starting chemicals showed in the above scheme.

Example 30

Synthesis of 2-chloro-4-((3S)-8-(4-(3-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)azetidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 372)

Cpd. No. 372 was prepared following the procedure of EXAMPLE 24 with the starting chemicals showed in the above scheme.

Example 31

Synthesis of 2-chloro-4-((3S)-8-(4-(4-(2-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)-2-oxoethyl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 402)

Compound 2 (1.0 eq.) was dissolved in DCM (5×). DIPEA (2.0 eq) was added followed by HATU (1.3 eq) and compound 3 (1.0 eq). The reaction mixture was allowed to stir for 0.5 h, and was concentrated to give syrup. The crude product was purified on a Combiflash chromatography system using hexane/EtOAc as the eluent to give compound 4. Compound 4 was dissolved in 10×DCM, and TFA (2×) was added. The reaction mixture was stirred at rt for 2 h. The solvent was distilled and dried on a lyophilizer overnight to give compound 5.

Compound 5 (1.5 eq) and compound 6 (1 eq) were dissolved in ACN, and Cs₂CO₃ (3.0 eq) was added. The reaction mixture was stirred at rt overnight. The reaction mixture was concentrated and purified by flash column chromatography on silica gel (Combiflash using MeOH and DCM as the eluent). The product was dissolved in 10×DCM, and TFA (2×) was added. The reaction mixture was stirred at rt for 2 h. The solvent was distilled and dried on a lyophilizer overnight to give compound 8.

Compound 8 (1.0 eq.) was dissolved in DCM (5×). DIPEA (2.0 eq) was added followed by HATU (1.3 eq). In a separate flask, compound 9 (1.0 eq) was dissolved in DMF (5×) and DIPEA (2.0 eq) was added slowly. The compound 9 solution was poured into the compound 8 solution, and the reaction mixture was allowed to stir for 0.5 h to give Cpd. No. 402 in 41% yield. UPLC-MS: 4.3 min, 817.424.

Example 33

Synthesis of 2-chloro-4-((3S)-8-(4-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-1,2,3,5,6,7-hexahydropyrrolo[3,4-f]isoindole-2-carbonyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 403)

Compound 2 (1.0 eq.) was dissolved in DCM (5×). DIPEA (2.0 eq) was added followed by HATU (1.3 eq) and compound 3 (1.0 eq). The above reaction mixture was allowed to stir for 0.5 h, and was concentrated to give syrup. The crude product was purified by Combiflash with hexane and EtOAc to give compound 4. The product was dissolved in 10×DCM, and TFA (4×) was added and stirring at rt for 2 h. The solvent was distilled and dried on the lyophilizer overnight to give compound 5.

Compound 5 (1.0 eq.) was dissolved in DCM (5×). DIPEA (2.0 eq) was added followed by HATU (1.3 eq). In a separate flask, compound 6 (1.0 eq) was dissolved in DMF (5×) and DIPEA (2.0 eq) was added slowly. The basified compound 6 solution was poured into the compound 5 solution, and the reaction mixture was allowed to stir for 0.5 h to give Cpd. No. 403 in 44% yield. UPLC-MS: 4.6 min, 802.40.

Example 34

Synthesis of 2-chloro-4-((3S)-8-(4-(4-(2-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)acetyl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 404)

Compound 1 (1.0 eq) and 2 (1.0 eq) were dissolved in DMF, and DIPEA (3.0 eq) was added. The reaction mixture was stirred at rt for 0.5 h. The reaction mixture was purified by prep HPLC with 28% of ACN in water. The compound was lyophilized to give 3. The product was dissolved in 10×DCM, and TFA (2×) was added and stirring at rt for 2 h. The solvent was distilled and dried on the lyophilizer overnight to give compound 4.

Compound 4 (1.0 eq.) was dissolved in DMF (5×). DIPEA (2.0 eq) was added followed by HATU (1.3 eq). In a separate flask, compound 5 (1.0 eq) was dissolved in DMF (5×) and DIPEA (2.0 eq) was added slowly. The basified compound 5 solution was poured into the compound 4 solution, and the reaction mixture was allowed to stir for 0.5 h to give Cpd. No. 404 in 40% yield. UPLC-MS: 4.1 min, 817.40.

Example 35

Synthesis of 2-chloro-4-((3S)-8-(6-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)pyridin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 417)

Step 1: Synthesis of (S)-5-(2-(3-chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)picolinic acid

(S)-2-Chloro-4-(3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile and tert-butyl 5-bromopicolinate were dissolved in dioxane. To the solution was added Pd₂(dba)₃ (10%), xantphos (10%), and Cs₂CO₃ (3 eq.), and the reaction mixture was stirred at 100° C. for 6 hours. The t-butyl ester was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. (S)-5-(2-(3-Chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)picolinic acid was obtained by removing the t-butyl group using TFA in DCM. ESI-MS: 410.15.

Step 2: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(3-(piperazin-1-yl)azetidin-1-yl)isoindoline-1,3-dione

tert-Butyl 4-(azetidin-3-yl)piperazine-1-carboxylate and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione were dissolved in DMSO. To the solution was added DIPEA (5 eq.), and the reaction mixture was stirred at 100° C. for 4 hours. Water was added. The reaction mixture and extracted by EA, and the organic phase was washed by water and dried by Na₂SO₄. The Boc protected compound was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. 2-(2,6-Dioxopiperidin-3-yl)-5-(3-(piperazin-1-yl)azetidin-1-yl)isoindoline-1,3-dione was obtained by removing the Boc group using TFA in DCM. ESI-MS: 397.18.

Step 3: Synthesis of 2-chloro-4-((3S)-8-(6-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)pyridin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 417)

(S)-5-(2-(3-Chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)picolinic acid and 2-(2,6-dioxopiperidin-3-yl)-5-(3-(piperazin-1-yl)azetidin-1-yl)isoindoline-1,3-dione were dissolved in DMF. To the solution was added DIPEA (5 eq.) and HATU (1.2 eq.), and the reaction mixture was stirred at r.t. for 1 hour. Water was added. The reaction mixture was extracted by EA, and the organic phase was washed by water and dried by Na₂SO₄. 2-Chloro-4-((3S)-8-(6-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)pyridin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. ESI-MS: 789.32.

Example 36

Synthesis of 2-chloro-4-((3S)-8-(4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)azetidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 407)

Step 1: Synthesis of (S)-2-chloro-4-(3-methyl-8-(4-(3-(piperazin-1-yl)azetidine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile

4-(2-(3-Chloro-4-cyanophenyl)-2,8-diazaspiro[4.5]decan-8-yl)benzoic acid and tert-butyl 4-(azetidin-3-yl)piperazine-1-carboxylate were dissolved in DMF. To the solution was added DIPEA (5 eq.) and HATU (1.2 eq.), and the reaction mixture was stirred at r.t. for 1 hour. Water was added. The reaction mixture was extracted by EA, and the organic phase was washed by water and dried by Na₂SO₄. The Boc protected compound was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. (S)-2-Chloro-4-(3-methyl-8-(4-(3-(piperazin-1-yl)azetidine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile was obtained by removing the Boc group using TFA in DCM. ESI-MS: 532.27.

Step 2: Synthesis of 2-chloro-4-((3S)-8-(4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)azetidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 407)

To a solution of (S)-2-chloro-4-(3-methyl-8-(4-(3-(piperazin-1-yl)azetidine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione in DMSO was added DIPEA (5 eq.). The reaction mixture was stirred at 100° C. for 12 hours. Water was added. The reaction mixture was extracted by EA, and the organic phase was washed by water and dried by Na₂SO₄. 2-Chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. ESI-MS: 788.32.

Example 37

Synthesis of 2-chloro-4-((3S)-8-(4-((1S,4S)-5-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 410)

Step 1: Synthesis of 5-(3-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

tert-Butyl (1S,4S)-5-(azetidin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione were dissolved in DMSO. To the solution was added DIPEA (5 eq.), and the reaction mixture was stirred at 100° C. for 4 hours. Water was added. The reaction mixture was extracted by EA, and the organic phase was washed by water and dried by Na₂SO₄. The Boc protected compound was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. 5-(3-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione was obtained by removing the Boc group using TFA in DCM. ESI-MS: 409.18.

Step 2: Synthesis of 2-chloro-4-((3S)-8-(4-((1S,4S)-5-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 410)

4-(2-(3-chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoic acid and 5-(3-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione were dissolved in DMF. To the solution was added DIPEA (5 eq.) and HATU (1.2 eq.), the reaction mixture was stirred at r.t. for 1 hour. Water was added. The reaction mixture was extracted by EA, and the organic phase was washed by water and dried by Na₂SO₄. 2-Chloro-4-((3S)-8-(4-((1S,4S)-5-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. ESI-MS: 800.32.

Example 38

Synthesis of 3-(4-(4-((S)-2-(3-chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoyl)piperazin-1-yl)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonitrile (Cpd. No. 431)

Step 1: Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-(piperazin-1-yl)azetidine-3-carbonitrile

tert-Butyl 4-(3-cyanoazetidin-3-yl)piperazine-1-carboxylate and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione were dissolved in DMSO. To the solution was added DIPEA (5 eq.), and the reaction mixture was stirred at 100° C. for 4 hours. Water was added. The reaction mixture was extracted by EA, and the organic phase was washed by water and dried by Na₂SO₄. The Boc protected compound was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. 1-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-(piperazin-1-yl)azetidine-3-carbonitrile was obtained by removing the Boc group using TFA in DCM. ESI-MS: 422.17.

Step 2: Synthesis of 3-(4-(4-((S)-2-(3-chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoyl)piperazin-1-yl)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonitrile (Cpd. No. 431)

4-(2-(3-chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoic acid and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-(piperazin-1-yl)azetidine-3-carbonitrile were dissolved in DMF. To the solution was added DIPEA (5 eq.) and HATU (1.2 eq.), and the reaction mixture was stirred at r.t. for 1 hour. Water was added. The reaction mixture was extracted by EA, and the organic phase was washed by water and dried by Na₂SO₄. 3-(4-(4-((S)-2-(3-Chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoyl)piperazin-1-yl)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonitrile was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. ESI-MS: 813.32.

Example 39

Synthesis of 2-chloro-4-((3S)-8-(4-(7-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)-2-azaspiro[3.5]nonane-2-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 408)

Step 1: Synthesis of (S)-2-chloro-4-(3-methyl-8-(4-(7-oxo-2-azaspiro[3.5]nonane-2-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile

(S)-4-(2-(3-chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoic acid and 2-azaspiro[3.5]nonan-7-one were dissolved in DMF. To the solution was added DIPEA (5 eq.) and HATU (1.2 eq.), and the reaction mixture was stirred at r.t. for 1 hour. Water was added. The reaction mixture was extracted by EA, and the organic phase was washed by water and dried by Na₂SO₄ to give (S)-2-chloro-4-(3-methyl-8-(4-(7-oxo-2-azaspiro[3.5]nonane-2-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. ESI-MS: 530.24.

Step 2: Synthesis of (S)-2-chloro-4-(3-methyl-8-(4-(7-oxo-2-azaspiro[3.5]nonane-2-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 408)

To a solution of (S)-2-chloro-4-(3-methyl-8-(4-(7-oxo-2-azaspiro[3.5]nonane-2-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile and 2-(2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione in DCE was added NaBH(OAc)₃ (1.5 eq.), AcOH, and TEA. The reaction mixture was stirred at r.t. for 6 hours. All volatiles were removed and the residue was chromatographed on silica gel to afford (S)-2-chloro-4-(3-methyl-8-(4-(7-oxo-2-azaspiro[3.5]nonane-2-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. ESI-MS: 813.34.

Example 40

Synthesis of 2-chloro-4-((3S)-8-(4-(6-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 409)

Step 1: Synthesis of (S)-2-chloro-4-(8-(4-(6-formyl-2-azaspiro[3.3]heptane-2-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile

(S)-4-(2-(3-chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoic acid and 2-azaspiro[3.5]nonan-7-one were dissolved in DMF. To the solution was added DIPEA (5 eq.) and HATU (1.2 eq.), and the reaction mixture was stirred at r.t. for 1 hour. Water was added. The reaction mixture was extracted by EA, and the organic phase was washed by water and dried by Na₂SO₄. The (S)-2-chloro-4-(8-(4-(6-formyl-2-azaspiro[3.3]heptane-2-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile was obtained by removing the solvent under vacuum and purified by flash column. ESI-MS: 516.23.

Step 2: Synthesis of 2-chloro-4-((3S)-8-(4-(6-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 409)

To a solution of (S)-2-chloro-4-(8-(4-(6-formyl-2-azaspiro[3.3]heptane-2-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile and 2-(2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione in DCE was added NaBH(OAc)₃ (1.5 eq.), AcOH, and TEA. The reaction mixture was stirred at r.t. for 6 hours. All volatiles were removed and the residue was chromatographed on silica gel to afford 2-chloro-4-((3S)-8-(4-(6-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. ESI-MS: 799.32.

Example 41

Synthesis of 4-((3S)-8-(4-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)-2-(trifluoromethyl)benzonitrile (Cpd. No. 420)

Step 1: Synthesis of (S)-4-(3-methyl-2,8-diazaspiro[4.5]decan-2-yl)-2-(trifluoromethyl)benzonitrile

4-fluoro-2-(trifluoromethyl)benzonitrile and tert-butyl (S)-3-methyl-2,8-diazaspiro[4.5]decane-8-carboxylate were dissolved in DMSO. To the solution was added DIPEA (5 eq.), and the reaction mixture was stirred at 100° C. for 4 hours. Water was added. The reaction mixture was extracted by EA, and the organic phase was washed by water and dried by Na₂SO₄. The Boc protected compound was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. (S)-4-(3-Methyl-2,8-diazaspiro[4.5]decan-2-yl)-2-(trifluoromethyl)benzonitrile was obtained by removing the Boc group using TFA in DCM. ESI-MS: 323.16.

Step 2: Synthesis of (S)-4-(2-(4-cyano-3-(trifluoromethyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-1 benzoic acid

(S)-4-(3-methyl-2,8-diazaspiro[4.5]decan-2-yl)-2-(trifluoromethyl)benzonitrile and tert-butyl 4-bromobenzoate were dissolved in dioxane. To the solution was added Pd₂(dba)₃ (10%), xantphos (10%), and Cs₂CO₃ (3 eq.), and the reaction mixture was stirred at 100° C. for 6 hours. The t-butyl ester was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. (S)-4-(2-(4-cyano-3-(trifluoromethyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoic acid was obtained by removing the t-butyl group using TFA in DCM. ESI-MS: 443.18.

Step 3: Synthesis of (S)-4-(3-methyl-8-(4-(4-oxopiperidine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)-2-(trifluoromethyl)benzonitrile

(S)-4-(2-(4-cyano-3-(trifluoromethyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoic acid and piperidin-4-one were dissolved in DMF. To the solution was added DIPEA (5 eq.) and HATU (1.2 eq.), and the reaction mixture was stirred at r.t. for 1 hour. Water was added. The reaction mixture was extracted by EA, and the organic phase was washed by water and dried by Na₂SO₄. (S)-4-(3-methyl-8-(4-(4-oxopiperidine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)-2-(trifluoromethyl)benzonitrile was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. ESI-MS: 524.24.

Step 4: Synthesis of 4-((3S)-8-(4-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)-2-(trifluoromethyl)benzonitrile (Cpd. No. 420)

To a solution of (S)-4-(3-methyl-8-(4-(4-oxopiperidine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)-2-(trifluoromethyl)benzonitrile and 2-(2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione in DCE was added NaBH(OAc)₃ (1.5 eq.), AcOH, and TEA. The reaction mixture was stirred at r.t. for 6 hours. All volatiles were removed and the residue was chromatographed on silica gel to afford 4-((3S)-8-(4-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)-2-(trifluoromethyl)benzonitrile. ESI-MS: 807.34.

Example 42

Synthesis of 4-((3S)-8-(4-(4-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)-2-(trifluoromethyl)benzonitrile (Cpd. No. 423)

Step 1: Synthesis of (S)-4-(8-(4-(4-formylpiperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)-2-(trifluoromethyl)benzonitrile

(S)-4-(2-(4-cyano-3-(trifluoromethyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoic acid and piperidine-4-carbaldehyde were dissolved in DMF. To the solution was added DIPEA (5 eq.) and HATU (1.2 eq.), and the reaction mixture was stirred at r.t. for 1 hour. Water was added. The reaction mixture was extracted by EA, and the organic phase was washed by water and dried by Na₂SO₄. (S)-4-(8-(4-(4-formylpiperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)-2-(trifluoromethyl)benzonitrile was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. ESI-MS: 538.26.

Step 2: Synthesis of 4-((3S)-8-(4-(4-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)-2-(trifluoromethyl)benzonitrile (Cpd. No. 423)

To a solution of (S)-4-(8-(4-(4-formylpiperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)-2-(trifluoromethyl)benzonitrile and 2-(2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione in DCE was added NaBH(OAc)₃ (1.5 eq.), AcOH, and TEA. The reaction mixture was stirred at r.t. for 6 hours. All volatiles were removed and the residue was chromatographed on silica gel to afford 4-((3S)-8-(4-(4-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)-2-(trifluoromethyl)benzonitrile. ESI-MS: 821.35.

Example 43

Synthesis of 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1,2,3,5,6,7-exahydrocyclopenta[f]isoindole-6-carbaldehyde

Step 1: Synthesis of diethyl 2,2-di(prop-2-yn-1-yl)malonate

To a suspension of sodium hydride (60% wt in mineral oil, 4.22 g, 105.5 mmol) in dry THF (100 mL) stirring at −10° C., dimethyl malonate (6.0 mL, 52.5 mmol) was added dropwise over 10 min. The reaction mixture was stirred at −10° C. for 5 min, and then propargyl bromide (80% wt. in toluene, 12.0 mL, 107.7 mmol) was added dropwise. The reaction mixture was warmed to 25° C. and stirred for 20 h. The reaction mixture was then poured into H₂O (50 mL) and Et₂O (50 mL), and the layers were separated. The aq layer was extracted with Et₂O (3×50 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO₄, filtered, and concentrated on a rotary evaporator leaving a white solid. The solid was recrystallized from ethyl acetate and hexanes resulting in 9.44 g of a crystalline white solid (84% yield).

Step 2: Synthesis of ethyl 2-(prop-2-yn-1-yl)pent-4-ynoate

Dimethyl 2,2-di(2-propynyl)malonate (4.70 g, 22.6 mmol) and lithium chloride (2.95 g, 69.7 mmol) were dissolved in a solution of H₂O (1.0 mL, 55.5 mmol) and DMSO (40 mL). This solution was then heated to reflux for 1 h. After cooling, the reaction mixture was poured into CHCl₃ (40 mL) and H₂O (40 mL). The layers were separated and the aq layer was extracted with CHCl₃ (3×40 mL). The combined organic layers were washed with H₂O (50 mL) and brine (50 mL), dried, filtered through silica gel, and concentrated, leaving a yellow oil. The crude oil was purified by flash chromatography on a silica gel column using 20% EtOAc in hexanes as S4 the eluent resulting in 3.06 g of a pale yellow oil (90% yield).

Step 3: Synthesis of ethyl 2-(prop-2-yn-1-yl)pent-4-yn-1-ol

To a suspension of lithium aluminum hydride (1.25 g, 33.0 mmol) in dry THF (40 mL) stirring at −10° C. was added a solution of methyl 2-(2-propynyl)-4-pentynoate (3.06 g, 20.4 mmol) in dry THF (10 mL). The reaction mixture was allowed to warm to 25° C. and stirred for 12 h. The reaction mixture was then quenched through the dropwise addition of H₂O (1.25 mL), an aq 10% NaOH solution (1.25 mL), and then additional H₂O (3.75 mL). The reaction mixture was then stirred for 30 min until the suspended solids turned white. The mixture was then filtered, and the solids were washed with diethyl ether (100 mL). The resulting solution was concentrated on a rotary evaporator yielding a pale yellow oil. The crude oil was purified by flash chromatography on a silica gel column using 10% EtOAc in hexanes as the eluent, resulting in 1.95 g of a clear oil (78% yield).

Step 4: Synthesis of dimethyl 2-(hydroxymethyl)-2,3-dihydro-1H-indene-5,6-dicarboxylate

A solution of 5 and dimethyl acetylenedicarboxylate (6, 30.7 g, 216 mmol) in 110 mL of absolute EtOH was degassed by bubbling N₂ through the solution for 10 min. To this was added 1.0 g (0.02 equiv) of Wilkinson's catalyst [(Ph₃P)₃RhCl] at 25° C. After being heated at reflux for 18 h, the reaction mixture was cooled to 25° C. and then concentrated in vacuo. The resulting brown residue was diluted in 200 mL of Et₂O, and the precipitate was removed by filtration over Celite. The filtrate was concentrated and the crude product purified by column chromatography (20% EtOAc/hexane) to give 4.60 g (26%) of compound 7.

Step 5: Synthesis of 2-(hydroxymethyl)-2,3-dihydro-1H-indene-5,6-dicarboxylic acid

NaOH (3N) was added to a solution of 7 in EtOH and stirred at 80° C. for 4 h. The EtOH was removed under reduced pressure, the pH was adjusted to acidity with 2M HCl, and the mixture was extracted with EtOAc. The solvent was removed to afford the product 8 which was used without further purification.

Step 6: Synthesis of 6-(hydroxymethyl)-6,7-dihydro-1H-indeno[5,6-c]furan-1,3(5H)-dione

The mixture of 8 in Ac₂O was stirred at 120° C. for 6 hours. All volatiles were removed and the residue was chromatographed on silica gel to afford 9.

Step 7: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-6-(hydroxymethyl)-6,7-dihydrocyclopenta[f]isoindole-1,3(2H,5H)-dione

To a solution of 9 and 10 in toluene was added TEA (3 eq.). The mixture was stirred at reflux for 8 hours. All volatiles were removed and the residue was chromatographed on silica gel to afford 11.

Step 8: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1,2,3,5,6,7-hexahydrocyclopenta[f]isoindole-6-carbaldehyde

To a solution of 11 in DCM was added DMP (1.2 eq.). The reaction mixture was stirred at reflux for 4 hours. All volatiles were removed and the residue was chromatographed on silica gel to afford 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1,2,3,5,6,7-hexahydrocyclopenta[f]isoindole-6-carbaldehyde. ESI-MS: 326.09.

Example 44

Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5,7-dihydrocyclopenta[f]isoindole-1,3,6(2H)-trione

Step 1: Synthesis of hepta-1,6-diyn-4-ol

To a solution of n-BuLi in hexane (6.2 eq., 75 mL) in Et₂O/hexane (100 mL) was added TMEDA (7.5 mL) and 2 (3.1 eq.) by dropwise at −78° C. The reaction mixture was stirred at −78° C. for 40 min, and then 12 in THF (20 mL) was added dropwise with 10 min. The reaction mixture was warmed to 25° C. and stirred for 2 h. The reaction mixture was then cooled to −78° C. and added 20 mL THF and Paraformaldehyde (13.5 g) in one portion. Then, the mixture was stirred at r.t. overnight. The mixture was added ice-cold NH₄Cl solution and extracted with Et₂O (3×50 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated on a rotary evaporator leaving a white solid. The solid was recrystallized from ethyl acetate and hexanes resulting in 13.

Step 2: Synthesis of dimethyl 2-hydroxy-2,3-dihydro-1H-indene-5,6-dicarboxylate

A solution of 13 and dimethyl acetylenedicarboxylate (6, 30.7 g, 216 mmol) in 110 mL of absolute EtOH was degassed by bubbling N₂ through the solution for 10 min. To this was added 1.0 g (0.02 equiv) of Wilkinson's catalyst [(Ph₃P)₃RhCl] at 25° C. After being warmed at reflux for 18 h, the reaction mixture was cooled to 25° C. and then concentrated in vacuo. The resulting brown residue was diluted in 200 mL of Et₂O, and the precipitate was removed by filtration over Celite. The filtrate was concentrated and the crude product purified by column chromatography (20% EtOAc/hexane) to give 4.60 g (26%) of compound 14.

Step 3: Synthesis of 2-hydroxy-2,3-dihydro-1H-indene-5,6-dicarboxylic acid

NaOH (3N) was added to a solution of 14 in EtOH and stirred at 80° C. for 4 h. Then the EtOH was removed under reduced pressure, the pH was adjusted to acidity with 2M HCl and the mixture was extracted with EtOAc. The solvent was removed to afford the product 15 which was used without further purification.

Step 4: Synthesis of 6-hydroxy-6,7-dihydro-1H-indeno[5,6-c]furan-1,3(5H)-dione

The mixture of 15 in Ac₂O was stirred at 120° C. for 6 hours. All volatiles were removed and the residue was chromatographed on silica gel to afford 16.

Step 5: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-6-hydroxy-6,7-dihydrocyclopenta[f]isoindole-1,3(2H,5H)-dione

To a solution of 16 and 10 in toluene was added TEA (3 eq.). The mixture was stirred at reflux for 8 hours. All volatiles were removed and the residue was chromatographed on silica gel to afford 17.

Step 6: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5,7-dihydrocyclopenta[f]isoindole-1,3,6(2H)-trione

To a solution of 17 in DCM was added DMP (1.2 eq.). The reaction mixture was stirred at reflux for 4 hours. All volatiles were removed and the residue was chromatographed on silica gel to afford intermediate 2-(2,6-dioxopiperidin-3-yl)-5,7-dihydrocyclopenta[f]isoindole-1,3,6(2H)-trione. ESI-MS: 312.07.

Example 45

Synthesis of 2-chloro-4-((3S)-8-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1,2,3,5,6,7-hexahydrocyclopenta[f]isoindol-6-yl)methyl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 428)

Step 1: Synthesis of (S)-2-chloro-4-(3-methyl-8-(4-(piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile

4-(2-(3-chloro-4-cyanophenyl)-2,8-diazaspiro[4.5]decan-8-yl)benzoic acid and tert-butyl piperazine-1-carboxylate were dissolved in DMF. To the solution was added DIPEA (5 eq.) and HATU (1.2 eq.), and the reaction mixture was stirred at r.t. for 1 hour. Water was added. The reaction mixture was extracted by EA, and the organic phase was washed by water and dried by Na₂SO₄. The Boc protected compound was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. (S)-2-Chloro-4-(3-methyl-8-(4-(piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile was obtained by removing the Boc group using TFA in DCM. ESI-MS: 477.23.

Step 2: Synthesis of 2-chloro-4-((3S)-8-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1,2,3,5,6,7-hexahydrocyclopenta[f]isoindol-6-yl)methyl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 428)

To a solution of (S)-2-chloro-4-(3-methyl-8-(4-(piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile and 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1,2,3,5,6,7-hexahydrocyclopenta[f]isoindole-6-carbaldehyde in DCE was added NaBH(OAc)₃ (1.5 eq.), AcOH, and TEA. The reaction mixture was stirred at r.t. for 6 hours. All volatiles were removed and the residue was chromatographed on silica gel to afford 2-chloro-4-((3S)-8-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1,2,3,5,6,7-hexahydrocyclopenta[f]isoindol-6-yl)methyl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. ESI-MS: 787.32.

Example 46

Synthesis of 2-chloro-4-((3S)-8-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1,2,3,5,6,7-hexahydrocyclopenta[f]isoindol-6-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 429)

To a solution of (S)-2-chloro-4-(3-methyl-8-(4-(piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile and 2-(2,6-dioxopiperidin-3-yl)-5,7-dihydrocyclopenta[f]isoindole-1,3,6(2H)-trione in DCE was added NaBH(OAc)₃ (1.5 eq.), AcOH, and TEA. The reaction mixture was stirred at r.t. for 6 hours. All volatiles were removed and the residue was chromatographed on silica gel to afford 2-chloro-4-((3S)-8-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1,2,3,5,6,7-hexahydrocyclopenta[f]isoindol-6-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. ESI-MS: 773.31.

Example 47

Synthesis of 2-chloro-4-((3S)-8-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 442) and 2-chloro-4-((3S)-8-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 444)

Example 48

Synthesis of 2-chloro-4-((3S)-8-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 443) and 2-chloro-4-((3S)-8-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 445)

Example 49

Synthesis of 2-chloro-4-((3S)-8-(2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1-carbonyl)pyrimidin-5-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 446)

Example 50

Synthesis of 2-chloro-4-((3S)-8-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1-carbonyl)pyridazin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 447)

Example 51

Synthesis of 2-chloro-4-((3S)-8-(5-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)pyridin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 505)

Step 1: Synthesis of (S)-6-(2-(3-chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)nicotinic acid

(S)-2-Chloro-4-(3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile and tert-butyl 6-fluoronicotinate were dissolved in DMSO. To the solution was added DIPEA (3 eq.), and the reaction mixture was stirred at 100° C. for 6 hours. The tert-butyl ester compound was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. (S)-6-(2-(3-chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)nicotinic acid was obtained by removing the tert-butyl group using TFA in DCM. ESI-MS: 410.15.

Step 2: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione

5,6-Difluoroisobenzofuran-1,3-dione and 3-aminopiperidine-2,6-dione hydrogen chloride were dissolved in toluene. To the solution was added TEA (5 eq.), and the reaction mixture was stirred at 100° C. for 4 hours. The final compound was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. ESI-MS: 294.05.

Step 3: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-6-(3-(piperazin-1-yl)azetidin-1-yl)isoindoline-1,3-dione

tert-Butyl 4-(azetidin-3-yl)piperazine-1-carboxylate and 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione were dissolved in DMSO. To the solution was added DIPEA (5 eq.), and the reaction mixture was stirred at 100° C. for 4 hours. Water was added to the reaction mixture. The reaction mixture was extracted with EA, and the collected organic phase was washed with water and dried with Na₂SO₄. The Boc protected compound was obtained by removing the solvent under vacuum and purified by flash column chromatography. 2-(2,6-Dioxopiperidin-3-yl)-5-fluoro-6-(3-(piperazin-1-yl)azetidin-1-yl)isoindoline-1,3-dione was obtained by removing the Boc group using TFA in DCM. ESI-MS: 415.17.

Step 4: Synthesis of 2-chloro-4-((3S)-8-(5-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)pyridin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 505)

(S)-6-(2-(3-Chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)nicotinic acid and 2-(2,6-dioxopiperidin-3-yl)-5-(3-(piperazin-1-yl)azetidin-1-yl)isoindoline-1,3-dione were dissolved in DMF. To the solution was added DIPEA (5 eq.) and HATU (1.2 eq.), and the reaction mixture was stirred at r.t. for 1 hour. Water was added to the reaction mixture. The reaction mixture was extracted with EA, and the collected organic phase was washed by water and dried with Na₂SO₄. 2-Chloro-4-((3S)-8-(5-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)pyridin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile was obtained by removing the solvent under vacuum and purifying by flash column chromatograph on silica gel. ESI-MS: 807.31.

Example 52

Synthesis of 2-chloro-4-((3S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)-2-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 510)

Step 1: Synthesis of (S)-4-(2-(3-chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)-3-fluorobenzoic acid

(S)-2-Chloro-4-(3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile and tert-butyl 4-bromo-3-fluorobenzoate were dissolved in dioxane. To the solution was added Pd₂(dba)₃ (10%), xantphos (10%), and Cs₂CO₃ (3 eq.), and the reaction mixture was stirred at 100° C. for 6 hours. The tert-butyl ester compound was obtained by removing the solvent under vacuum and purified by flash column chromatography on silica gel. (S)-4-(2-(3-Chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)-3-fluorobenzoic acid was obtained by removing the Boc group using TFA in DCM. ESI-MS: 427.15.

Step 2: Synthesis of 2-chloro-4-((3S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)-2-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 510)

(S)-4-(2-(3-Chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)-3-fluorobenzoic acid and 2-(2,6-dioxopiperidin-3-yl)-5-(3-(piperazin-1-yl)azetidin-1-yl)isoindoline-1,3-dione were dissolved in DMF. To the solution was added DIPEA (5 eq.) and HATU (1.2 eq.), and the reaction mixture was stirred at r.t. for 1 hour. Water was added to the reaction mixture. The reaction mixture was extracted with EA, and the collected organic phase was washed with water and dried with Na₂SO₄. The 2-chloro-4-((3S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)-2-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile was obtained by removing the solvent under vacuum and purifying by flash column chromatography on silica gel. ESI-MS: 806.31.

Example 53

Synthesis of 2-Chloro-4-((3S)-8-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3,5,6,8,9-hexahydroazepino[4,5-f]isoindol-7(1H)-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 558)

Compounds 1 (1.0 eq) and 2 (2.0 eq) were dissolved in DCE (20×), and AcOH (2.0 eq) was added. After 12 h at room temperature, NaB(OAc)₃H (4.0 eq) was added. After 2 h, the volatiles were removed and the residue was purified using a Combiflash chromatography system (DCM and MeOH) to give compound 3 in 65% yield.

Compound 3 was dissolved in DCM (10×) and TFA (5×) was added at ambient temperature. The volatiles were removed to give compound 4 in 100% yield.

Compound 5 (1.0 eq), DIPEA (3.0 eq), and HATU (1.4 eq) were dissolved in DMF. After 10 mins, compound 4 (1.0 eq) was added. After 2 h, the reaction mixture was acidified by TFA and purified by preparative HPLC using 45% acetonitrile in water as the eluent to give Cpd. No. 558.

Example 54

Synthesis of 2-chloro-4-((3S)-8-(6-(1′-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[4,4′-bipiperidine]-1-carbonyl)pyridazin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile (Cpd. No. 568)

Compound 1 (1.0 eq), compound 2 (1.3 eq), and Cs₂CO₃ (3.0 eq) were dissolved in DMF and stirred for 4 h at 60° C. The reaction mixture was partitioned between EtOAc and H₂O. The organic layer was separated, concentrated, purified using Combiflash chromatography system (hexane and EtOAc) to give ester of compound 3. The ester was dissolved in water, MeOH, and THF, and NaOH (3 N) was added. After 4 h, the reaction mixture was acidified using HCl to pH 1. The volatiles were removed and residue was purified by column column chromatography on silica gel (DCM and MeOH) to give compound 3 in 80% yield.

Compound 3 (1.0 eq), DIPEA (3.0 eq), and HATU (1.4 eq) were dissolved in DMF. After 10 mins, compound 4 (1.0 eq) was added. The reaction was complete in 0.5 h, and the volatiles were removed. The residue was purified using a Combiflash chromatography system (DCM and MeOH) to give compound 5 in 70%.

Compound 5 was dissolved in DCM (10×) and TFA (5X×) was added at ambient temperature. The volatiles were removed to give compound 6 in 100% yield.

Compound 6 (1.0 eq) and DIPEA (4.0 eq) were dissolved in DMF, and compound 7 (1.5 eq) was added. The mixture was stirred at 90° C. for 12 h. UPLC-MS indicated complete conversion of compound 6. The reaction was cooled to rt, acidified with TFA, and purified by preparative HPLC (46% acetonitrile) to give Cpd. No. 568 in 65% yield.

Example 55

Analytical Characterization of Representative Compounds of the Disclosure

The following Compounds of the Disclosure were prepared using the methods described in the EXAMPLEs above and/or synthetic reagents and techniques known in the art.

Cpd. No. 2: 2-chloro-4-(8-(4-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 816.39; calcd: 816.36; >95% purity.

Cpd. No. 4: 2-chloro-4-(8-(4-(5-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 843.41; calcd: 843.37; >95% purity.

Cpd. No. 5: 2-chloro-4-(8-(4-(5-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 815.37; calcd: 815.34; >95% purity.

Cpd. No. 6: 2-chloro-4-(8-(3-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 817.33; calcd: 817.36; >95% purity.

Cpd. No. 7: 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-4-fluoropiperidin-4-yl)methyl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 835.39; calcd: 835.35; >95% purity.

Cpd. No. 8: 5-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-4-fluoropiperidin-4-yl)methyl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)-3-(trifluoromethyl)picolinonitrile. LC-MS (ESI) m/z (M+H)⁺: 870.33; calcd: 870.37; >95% purity.

Cpd. No. 9: 5-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)-3-(trifluoromethyl)picolinonitrile. LC-MS (ESI) m/z (M+H)⁺: 824.39; calcd: 824.35; >95% purity.

Cpd. No. 10: 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-fluoroazetidin-3-yl)methyl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 807.35; calcd: 807.32; >95% purity.

Cpd. No. 11: 5-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-fluoroazetidin-3-yl)methyl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)-3-(trifluoromethyl)picolinonitrile. LC-MS (ESI) m/z (M+H)⁺: 842.31; calcd: 842.34; >95% purity.

Cpd. No. 12: 5-(2-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-fluoroazetidin-3-yl)methyl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-8-yl)-3-(trifluoromethyl)picolinonitrile. LC-MS (ESI) m/z (M+H)⁺: 842.38; calcd: 842.34; >95% purity.

Cpd. No. 13: 5-(2-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-4-fluoropiperidin-4-yl)methyl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-8-yl)-3-(trifluoromethyl)picolinonitrile. LC-MS (ESI) m/z (M+H)⁺: 870.41; calcd: 870.37; >95% purity.

Cpd. No. 14: 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-methylazetidin-3-yl)methyl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 803.37; calcd: 803.34; >95% purity.

Cpd. No. 15: 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-4-methoxypiperidin-4-yl)methyl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 847.32; calcd: 847.37; >95% purity.

Cpd. No. 16: 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-4-methylpiperidin-4-yl)methyl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 831.33; calcd: 831.37; >95% purity.

Cpd. No. 17: 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-methoxyazetidin-3-yl)methyl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 819.38; calcd: 819.34; >95% purity.

Cpd. No. 18: 2-chloro-4-(8-(4-(5-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 801.37; calcd: 801.33; >95% purity.

Cpd. No. 19: 2-chloro-4-(8-(4-(4-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)azetidin-3-yl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 858.42; calcd: 858.39; >95% purity.

Cpd. No. 20: 2-chloro-4-(8-(4-(4-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 858.41; calcd: 858.39; >95% purity.

Cpd. No. 21: 2-chloro-4-(8-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-2-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 760.34; calcd: 760.30; >95% purity.

Cpd. No. 22: 2-chloro-4-(8-(4-(5-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 829.39; calcd: 829.36; >95% purity.

Cpd. No. 23: 2-chloro-4-(8-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 760.33; calcd: 760.30; >95% purity.

Cpd. No. 24: 2-chloro-4-(8-(4-(4-(((3R)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 803.37; calcd: 803.34; >95% purity.

Cpd. No. 25: 2-chloro-4-(8-(4-(4-(((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidin-3-yl)methyl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 803.38; calcd: 803.34; >95% purity.

Cpd. No. 26: 2-chloro-4-(8-(4-(4-(2-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)-2-oxoethyl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 803.33; calcd: 803.31; >95% purity.

Cpd. No. 27: 2-chloro-4-(8-(6-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)nicotinoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 818.37; calcd: 818.35; >95% purity.

Cpd. No. 28: 2-chloro-4-(8-(6-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)nicotinoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 790.34; calcd: 790.32; >95% purity.

Cpd. No. 29: 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)-3-fluorobenzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 835.37; calcd: 835.35; >95% purity.

Cpd. No. 30: 5-(8-(6-(4-((1-(2-(2,4-dioxocyclohexyl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)nicotinoyl)-2,8-diazaspiro[4.5]decan-2-yl)-3-(trifluoromethyl)picolinonitrile. LC-MS (ESI) m/z (M+H)⁺: 852.41; calcd: 852.38; >95% purity.

Cpd. No. 31: 4-(8-(4-(4-((1-(2-(2,4-dioxocyclohexyl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)-2-(trifluoromethyl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 850.37; calcd: 850.39; >95% purity.

Cpd. No. 32: 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 775.33; calcd: 775.31; >95% purity.

Cpd. No. 33: 2-chloro-4-(8-(4-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1,2,3,5,7,8-hexahydro-6H-pyrrolo[3,4-g]isoquinolin-6-yl)-2-oxoethyl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 817.34; calcd: 817.32; >95% purity.

Cpd. No. 34: 4-(8-(6-(4-((1-(2-(2,4-dioxocyclohexyl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)nicotinoyl)-2,8-diazaspiro[4.5]decan-2-yl)-2-(trifluoromethyl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 851.42; calcd: 851.39; >95% purity.

Cpd. No. 35: 2-chloro-4-(8-(2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)pyrimidine-5-carbonyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 819.37; calcd: 819.35; >95% purity.

Cpd. No. 36: 2-chloro-4-(8-(4-((4-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)bicyclo[2.2.2]octan-1-yl)ethynyl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 823.32; calcd: 823.34; >95% purity.

Cpd. No. 37: 2-chloro-4-(8-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 817.39; calcd: 817.36; >95% purity.

Cpd. No. 38: 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 807.34; calcd: 807.32; >95% purity.

Cpd. No. 39: 2-chloro-4-(8-(4-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidin-4-yl)ethynyl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 798.34; calcd: 798.32; >95% purity.

Cpd. No. 40: 2-chloro-4-(8-(4-((1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)azetidin-3-yl)ethynyl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 798.35; calcd: 798.32; >95% purity.

Cpd. No. 41: 2-chloro-4-(8-(4-((1′-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-[1,4′-bipiperidin]-4-yl)ethynyl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 826.37; calcd: 826.35; >95% purity.

Cpd. No. 42: 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 817.39; calcd: 817.36; >95% purity.

Cpd. No. 43: 2-chloro-4-(8-(4-(((1r,4r)-4-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)cyclohexyl)ethynyl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 797.35; calcd: 797.32; >95% purity.

Cpd. No. 45: 2-chloro-4-(8-(3-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 817.38; calcd: 817.36; >95% purity.

Cpd. No. 46: 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-1-azaspiro[3.3]heptan-6-yl)methyl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 829.35; calcd: 829.36; >95% purity.

Cpd. No. 47: 2-chloro-4-(8-(4-(5-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-1,5-diazocane-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 831.34; calcd: 831.37; >95% purity.

Cpd. No. 48: 2-chloro-4-(8-(4-(5-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 829.39; calcd: 829.36; >95% purity.

Cpd. No. 49: 2-chloro-4-(8-(4-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-2,6-diazaspiro[3.4]octane-6-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 829.38; calcd: 829.36; >95% purity.

Cpd. No. 50: 2-chloro-4-(8-(4-(7-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-3,7-diazabicyclo[3.3.1]nonane-3-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 843.40; calcd: 843.37; >95% purity.

Cpd. No. 51: 2-chloro-4-(8-(4-(8-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 857.41; calcd: 857.39; >95% purity.

Cpd. No. 53: 5-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)-3-(trifluoromethyl)picolinonitrile. LC-MS (ESI) m/z (M+H)⁺: 838.35; calcd: 838.37; >95% purity.

Cpd. No. 54: 2-(difluoromethyl)-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 833.38; calcd: 833.40; >95% purity.

Cpd. No. 55: 5-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)-3-(trifluoromethyl)picolinonitrile. LC-MS (ESI) m/z (M+H)⁺: 852.36; calcd: 852.38; >95% purity.

Cpd. No. 56: 2-chloro-4-(8-(4-((3aR,6aS)-5-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 829.38; calcd: 829.36; >95% purity.

Cpd. No. 57: 2-chloro-4-(8-(4-(8-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)-2,8-diazaspiro[4.5]decan-2-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 829.39; calcd: 829.36; >95% purity.

Cpd. No. 58: 2-(difluoromethyl)-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 819.36; calcd: 819.38; >95% purity.

Cpd. No. 59: 2-(difluoromethyl)-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 833.42; calcd: 833.40; >95% purity.

Cpd. No. 60: 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-1,4-diazepane-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 817.39; calcd: 817.36; >95% purity.

Cpd. No. 61: 2-chloro-4-(8-(4-(6-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 815.37; calcd: 815.34; >95% purity.

Cpd. No. 62: 5-(2-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-8-yl)-3-(trifluoromethyl)picolinonitrile. LC-MS (ESI) m/z (M+H)⁺: 838.39; calcd: 838.37; >95% purity.

Cpd. No. 64: 2-chloro-4-(8-(4-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-azaspiro[3.3]heptan-6-yl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 815.37; calcd: 815.34; >95% purity.

Cpd. No. 65: 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)-2-fluorophenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 821.36; calcd: 821.33; >95% purity.

Cpd. No. 66: 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)-3-fluorophenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 821.35; calcd: 821.33; >95% purity.

Cpd. No. 67: 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-1-carbonyl)-2-fluorophenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 835.34; calcd: 835.35; >95% purity.

Cpd. No. 68: 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-1-carbonyl)-3-fluorophenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 835.37; calcd: 835.35; >95% purity.

Cpd. No. 69: 2-chloro-4-(8-(4-(((1r,4r)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1,2,3,5,7,8-hexahydro-6H-pyrrolo[3,4-g]isoquinolin-6-yl)methyl)cyclohexyl)ethynyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 783.36; calcd: 783.34; >95% purity.

Cpd. No. 70: 5-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)-3-(trifluoromethyl)picolinonitrile. LC-MS (ESI) m/z (M+H)⁺: 838.39; calcd: 838.37; >95% purity.

Cpd. No. 71: 5-(2-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-8-yl)-3-(trifluoromethyl)picolinonitrile. LC-MS (ESI) m/z (M+H)⁺: 838.36; calcd: 838.37; >95% purity.

Cpd. No. 73: 4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)-2-(trifluoromethyl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 851.37; calcd: 851.39; >95% purity.

Cpd. No. 74: 4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)-2-(trifluoromethyl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 837.35; calcd: 837.37; >95% purity.

Cpd. No. 75: 2-chloro-4-(8-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 803.37; calcd: 803.34; >95% purity.

Cpd. No. 76: 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 831.36; calcd: 831.34; >95% purity.

Cpd. No. 77: 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 821.35; calcd: 821.33; >95% purity.

Cpd. No. 78: 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-1-carbonyl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 845.37; calcd: 845.35; >95% purity.

Cpd. No. 79: 5-(2-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-8-yl)-3-(trifluoromethyl)picolinonitrile. LC-MS (ESI) m/z (M+H)⁺: 838.40; calcd: 838.37; >95% purity.

Cpd. No. 80: 2-chloro-4-(8-(4-((4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)sulfonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 853.33; calcd: 853.33; >95% purity.

Cpd. No. 81: 2-chloro-4-(8-(3-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 831.32; calcd: 831.34; >95% purity.

Cpd. No. 82: 2-chloro-4-(8-(3-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-1-carbonyl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 845.36; calcd: 845.35; >95% purity.

Cpd. No. 83: 2-chloro-4-(8-(3-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazine-1-carbonyl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 817.35; calcd: 817.32; >95% purity.

Cpd. No. 84: 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-fluoroazetidin-3-yl)methyl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 807.34; calcd: 807.32; >95% purity.

Cpd. No. 85: 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-methylazetidin-3-yl)methyl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 803.31; calcd: 803.34; >95% purity.

Cpd. No. 86: 2-chloro-4-(8-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 817.39; calcd: 817.36; >95% purity.

Cpd. No. 87: 2-chloro-4-(8-(4-(6-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 787.33; calcd: 787.31; >95% purity.

Cpd. No. 88: 2-chloro-4-(8-(4-((3aR,6aR)-5-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 829.37; calcd: 829.36; >95% purity.

Cpd. No. 89: 2-chloro-4-(8-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carbonyl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 748.29; calcd: 748.27; >95% purity.

Cpd. No. 90: 2-chloro-4-(8-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carbonyl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 748.28; calcd: 748.27; >95% purity.

Cpd. No. 91: 2-chloro-4-(8-(4-((3aR,6aS)-5-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-3a,6a-dimethyloctahydropyrrolo[3,4-c]pyrrole-2-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 857.37; calcd: 857.39; >95% purity.

Cpd. No. 92: 2-chloro-4-(8-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 720.25; calcd: 720.27; >95% purity.

Cpd. No. 93: 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-methoxyazetidin-3-yl)methyl)piperazin-1-yl)benzoyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 819.35; calcd: 819.34; >95% purity.

Cpd. No. 94: 2-chloro-4-(8-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1,2,3,5,7,8-hexahydro-6H-pyrrolo[3,4-g]isoquinolin-6-yl)methyl)piperidine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 788.36; calcd: 788.33; >95% purity.

Cpd. No. 95: 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazin-1-yl)benzoyl)-3-oxo-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 817.34; calcd: 817.32; >95% purity.

Cpd. No. 96: 2-chloro-4-(8-(4-(3-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)azetidine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 732.26; calcd: 732.27; >95% purity.

Cpd. No. 97: 2-chloro-4-(8-(4-(6-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)-2-azaspiro[3.3]heptane-2-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 772.32; calcd: 772.30; >95% purity.

Cpd. No. 98: 2-chloro-4-(8-(4-(6-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 786.34; calcd: 786.32; >95% purity.

Cpd. No. 99: 2-chloro-4-(8-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1,2,3,5,7,8-hexahydro-6H-pyrrolo[3,4-g]isoquinolin-6-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 800.32; calcd: 800.33; >95% purity.

Cpd. No. 100: 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)benzoyl)-3-oxo-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 831.37; calcd: 831.34; >95% purity.

Cpd. No. 101: 2-chloro-4-(8-(4-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)piperidin-1-yl)benzoyl)-3-oxo-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 774.31 calcd: 774.28; >95% purity.

Cpd. No. 102: 2-chloro-4-(8-(4-(3-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)azetidine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 746.27; calcd: 746.29; >95% purity.

Cpd. No. 103: 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)-1,4-diazepane-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 789.35; calcd: 789.33; >95% purity.

Cpd. No. 104: 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-4-methoxypiperidin-4-yl)methyl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 847.35; calcd: 847.37; >95% purity.

Cpd. No. 105: 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-4-fluoropiperidin-4-yl)methyl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 835.33; calcd: 835.35; >95% purity.

Cpd. No. 106: 2-chloro-4-(8-(4-(4-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)piperidine-1-carbonyl)-3-fluorophenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 792.33; calcd: 792.31; >95% purity.

Cpd. No. 107: 2-chloro-4-(8-(4-(4-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)piperidine-1-carbonyl)-2-fluorophenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 792.32; calcd: 792.31; >95% purity.

Cpd. No. 108: 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)-3-methylbenzonitrile. LC-MS (ESI) m/z (M+H)⁺: 803.36; calcd: 803.34; >95% purity.

Cpd. No. 110: 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)-3-methylbenzonitrile. LC-MS (ESI) m/z (M+H)⁺: 835.38; calcd: 835.35; >95% purity.

Cpd. No. 111: 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)-3-methylbenzonitrile. LC-MS (ESI) m/z (M+H)⁺: 849.39; calcd: 849.37; >95% purity.

Cpd. No. 113: 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazin-1-yl)benzoyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 817.39; calcd: 817.36; >95% purity.

Cpd. No. 115: 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)benzoyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 831.35; calcd: 831.37; >95% purity.

Cpd. No. 116: 2-chloro-4-(8-(4-((1S,4S)-5-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 815.36; calcd: 815.34; >95% purity.

Cpd. No. 117: 2-chloro-4-(8-(4-(1′-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-[3,3′-biazetidine]-1-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 746.31; calcd: 746.29; >95% purity.

Cpd. No. 118: 2-chloro-4-(8-(4-((1R,4R)-5-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)phenyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 815.36; calcd: 815.34; >95% purity.

Cpd. No. 119: 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 835.36; calcd: 835.35; >95% purity.

Cpd. No. 121: 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazin-1-yl)benzoyl)-1-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 817.37; calcd: 817.35; >95% purity.

Cpd. No. 122: 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazin-1-yl)benzoyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 789.35; calcd: 789.33; >95% purity.

Cpd. No. 123: 2-chloro-4-(8-((1r,4r)-4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)cyclohexyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 795.35; calcd: 795.37; >95% purity.

Cpd. No. 124: 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazin-1-yl)benzoyl)-1-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 789.34; calcd: 789.33; >95% purity.

Cpd. No. 125: 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazine-1-carbonyl)phenyl)-1-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 803.35; calcd: 803.34; >95% purity.

Cpd. No. 126: 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)benzoyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 803.36; calcd: 803.34; >95% purity.

Cpd. No. 127: 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)benzoyl)-1-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 831.40; calcd: 831.37; >95% purity.

Cpd. No. 128: 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazin-1-yl)benzoyl)-1-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 803.36; calcd: 803.34; >95% purity.

Cpd. No. 129: 2-chloro-4-(8-(4-((1S,4S)-5-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 829.38; calcd: 829.36; >95% purity.

Cpd. No. 130: 2-chloro-4-(8-(4-((1R,4R)-5-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 829.35; calcd: 829.36; >95% purity.

Cpd. No. 289: 2-chloro-4-(8-(4-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)piperidin-1-yl)benzoyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 774.34; calcd: 774.32; >95% purity.

Cpd. No. 290: 2-chloro-4-(8-(4-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)piperidin-1-yl)benzoyl)-1-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 774.36; calcd: 774.32; >95% purity.

Cpd. No. 291: 2-chloro-4-(8-(4-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)piperidine-1-carbonyl)-3-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 792.35; calcd: 792.31; >95% purity.

Cpd. No. 292: 2-chloro-4-(8-(4-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)piperidine-1-carbonyl)-2-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 792.36; calcd: 792.31; >95% purity.

Cpd. No. 294: 2-chloro-4-((3R)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 789.36; calcd: 789.33; >95% purity.

Cpd. No. 295: 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)-3-methylbenzonitrile. LC-MS (ESI) m/z (M+H)⁺: 803.39; calcd: 803.34; >95% purity.

Cpd. No. 296: 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 807.36; calcd: 807.32; >95% purity.

Cpd. No. 345: 2-chloro-4-((3R)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 807.35; calcd: 807.32; >95% purity.

Cpd. No. 344: 2-chloro-4-((3S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 807.34; calcd: 807.32; >95% purity.

Cpd. No. 346: 2-chloro-4-((3S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 775.39; calcd: 775.35; >95% purity.

Cpd. No. 347: 2-chloro-4-((3S)-8-(4-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)piperidin-1-yl)benzoyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 774.36; calcd: 774.32; >95% purity.

Cpd. No. 348: 2-chloro-4-((3S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 775.33; calcd: 775.35; >95% purity.

Cpd. No. 349: 2-chloro-4-((3S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)-3-methylbenzonitrile. LC-MS (ESI) m/z (M+H)⁺: 803.37; calcd: 803.34; >95% purity.

Cpd. No. 350: 2-chloro-4-((1S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-1-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 789.35; calcd: 789.33; >95% purity.

Cpd. No. 351: 2-chloro-4-((1R)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-1-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 789.36; calcd: 789.33; >95% purity.

Cpd. No. 352: 4-((3S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)-2-(trifluoromethyl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 823.37; calcd: 823.35; >95% purity.

Cpd. No. 353: 2-(difluoromethyl)-4-((3S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 805.39; calcd: 805.36; >95% purity.

Cpd. No. 354: 5-((3S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)-3-(trifluoromethyl)picolinonitrile. LC-MS (ESI) m/z (M+H)⁺: 824.37; calcd: 824.35; >95% purity.

Cpd. No. 150: 2-chloro-4-(8-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile; ¹H NMR (400 MHz, MeOD) δ 7.81 (d, J=9.2 Hz, 2H), 7.70 (d, J=9.0 Hz, 2H), 7.55-7.50 (m, 2H), 7.37-7.02 (m, 4H), 6.92-6.52 (m, 3H), 6.66-6.41 (m, 2H), 5.17-5.12 (m, 3H), 4.78-4.20 (m, 4H), 3.66-3.30 (m, 10H), 2.98-2.77 (m, 10H), 2.88-2.02 (m, 4H), 2.34-1.32 (m, 5H), ESI-MS: 803.40.

Cpd. No. 144: 2-chloro-4-((2-(4-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)piperidine-1-carbonyl)phenyl)-2-azaspiro[3.5]nonan-7-yl)oxy)benzonitrile; ¹H NMR (400 MHz, MeOD) δ 7.97 (s, 2H), 7.72 (d, J=8.8 Hz, 2H), 7.49-7.40 (m, 2H), 7.22-7.14 (m, 2H), 6.99-6.76 (m, 2H), 3.49-3.30 (m, 13H), 2.87-1.54 (m, 17H), ESI-MS: 761.44.

Cpd. No. 143: 2-chloro-4-((2-(4-(4-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)piperidine-1-carbonyl)phenyl)-2-azaspiro[3.5]nonan-7-yl)oxy)benzonitrile; ¹H NMR (400 MHz, MeOD) δ 8.00 (s, 2H), 7.74 (d, J=9.0 Hz, 2H), 7.47-7.42 (m, 2H), 7.24-7.10 (m, 2H), 7.01-6.85 (m, 2H), 3.50-3.47 (m, 8H), 3.45-3.22 (m, 5H), 2.66-1.35 (m, 19H), ESI-MS: 775.34.

Cpd. No. 142: 2-chloro-4-((2-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)phenyl)-2-azaspiro[3.5]nonan-7-yl)oxy)benzonitrile; ¹H NMR (400 MHz, MeOD) δ 7.74 (d, J=8.8 Hz, 2H), 7.70-7.60 (m, 4H), 7.14-7.13 (m, 2H), 7.05-6.93 (m, 2H), 4.94-4.88 (m, 1H), 3.85-3.11 (m, 13H), 2.94-2.22 (m, 9H), 2.01-1.35 (m, 12H), ESI-MS: 804.44.

Cpd. No. 141: 2-chloro-4-((2-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-1-carbonyl)phenyl)-2-azaspiro[3.5]nonan-7-yl)oxy)benzonitrile; ¹H NMR (400 MHz, MeOD) δ 7.75 (d, J=9.2 Hz, 2H), 7.74-7.62 (m, 4H), 7.13-7.10 (m, 2H), 7.00-6.88 (m, 2H), 4.97-4.90 (m, 1H), 3.83-3.07 (m, 13H), 2.98-2.29 (m, 9H), 2.11-1.29 (m, 14H), ESI-MS: 818.40.

Cpd. No. 145: 2-chloro-4-(7-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-1-carbonyl)phenoxy)-2-azaspiro[3.5]nonan-2-yl)benzonitrile; ¹H NMR (400 MHz, MeOD) δ 7.76 (d, J=9.0 Hz, 2H), 7.64-7.55 (m, 2H), 7.42-7.37 (m, 2H), 7.15-7.11 (m, 2H), 7.02-6.80 (m, 2H), 4.99-4.88 (m, 1H), 3.77-3.47 (m, 11H), 3.22-2.41 (m, 13H), 2.22-1.39 (m, 12H), ESI-MS: 818.42.

Cpd. No. 146: 2-chloro-4-(7-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)phenoxy)-2-azaspiro[3.5]nonan-2-yl)benzonitrile; ¹H NMR (400 MHz, MeOD) δ 7.76 (d, J=8.4 Hz, 2H), 7.76-7.58 (m, 4H), 7.16-7.11 (m, 2H), 6.99-6.88 (m, 2H), 4.95-4.90 (m, 1H), 3.80-3.10 (m, 15H), 3.08-2.44 (m, 7H), 2.01-1.35 (m, 12H), ESI-MS: 804.42.

Cpd. No. 147: 2-chloro-4-(7-(4-(4-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)piperidine-1-carbonyl)phenoxy)-2-azaspiro[3.5]nonan-2-yl)benzonitrile; ESI-MS: 775.30.

Cpd. No. 148: 2-chloro-4-(7-(4-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)piperidine-1-carbonyl)phenoxy)-2-azaspiro[3.5]nonan-2-yl)benzonitrile; ESI-MS: 761.30.

Cpd. No. 137: 2-chloro-4-(8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)bicyclo[2.2.2]octane-1-carbonyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile; ¹H NMR (400 MHz, MeOD) δ 7.87 (d, J=9.0 Hz, 1H), 7.56-7.12 (m, 4H), 6.97-6.88 (m, 2H), 4.97-4.90 (m, 1H), 3.80-3.02 (m, 17H), 3.71-2.47 (m, 7H), 2.21-1.35 (m, 22H), ESI-MS: 863.39.

Cpd. No. 138: 2-chloro-4-(8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-1-carbonyl)bicyclo[2.2.2]octane-1-carbonyl)-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile; ESI-MS: 877.42.

Cpd. No. 152: ESI-MS [M+H]: 817.43.

Cpd. No. 153: ESI-MS [M+H]: 826.54.

Cpd. No. 154: ESI-MS [M+H]: 803.65.

Cpd. No. 155: ESI-MS [M+H]: 812.30.

Cpd. No. 156: ESI-MS [M+H]: 812.36.

Cpd. No. 157: ESI-MS [M+H]: 835.37.

Cpd. No. 158: ESI-MS [M+H]: 835.35.

Cpd. No. 159: ESI-MS [M+H]: 852.39.

Cpd. No. 160: ESI-MS [M+H]: 852.27.

Cpd. No. 161: ESI-MS [M+H]: 857.36.

Cpd. No. 162: ESI-MS [M+H]: 835.47.

Cpd. No. 163: ESI-MS [M+H]: 870.43.

Cpd. No. 164: ESI-MS [M+H]: 870.31.

Cpd. No. 165: ESI-MS [M+H]: 804.35.

Cpd. No. 166: ESI-MS [M+H]: 829.47.

Cpd. No. 167: ESI-MS [M+H]: 802.29.

Cpd. No. 168: ESI-MS [M+H]: 838.47.

Cpd. No. 169: ESI-MS [M+H]: 831.28.

Cpd. No. 170: ESI-MS [M+H]: 866.61.

Cpd. No. 171: ESI-MS [M+H]: 866.47.

Cpd. No. 172: ESI-MS [M+H]: 853.36.

Cpd. No. 173: ESI-MS [M+H]: 888.34.

Cpd. No. 174: ESI-MS [M+H]: 888.20.

Cpd. No. 175: ESI-MS [M+H]: 798.37.

Cpd. No. 176: ESI-MS [M+H]: 798.28.

Cpd. No. 177: ESI-MS [M+H]: 852.32.

Cpd. No. 178: ESI-MS [M+H]: 852.41.

Cpd. No. 179: ESI-MS [M+H]: 864.38.

Cpd. No. 180: ESI-MS [M+H]: 774.29.

Cpd. No. 181: ESI-MS [M+H]: 788.22.

Cpd. No. 182: ESI-MS [M+H]: 802.48.

Cpd. No. 183: ESI-MS [M+H]: 760.35.

Cpd. No. 184: ESI-MS [M+H]: 774.29.

Cpd. No. 185: ESI-MS [M+H]: 788.28.

Cpd. No. 186: ESI-MS [M+H]: 817.39.

Cpd. No. 187: ESI-MS [M+H]: 831.37.

Cpd. No. 188: ESI-MS [M+H]: 867.46.

Cpd. No. 189: ESI-MS [M+H]: 881.37.

Cpd. No. 190: ESI-MS [M+H]: 817.38.

Cpd. No. 191: ESI-MS [M+H]: 831.48.

Cpd. No. 192: ESI-MS [M+H]: 817.28.

Cpd. No. 193: ESI-MS [M+H]: 831.39.

Cpd. No. 194: ESI-MS [M+H]: 835.45.

Cpd. No. 195: ESI-MS [M+H]: 849.63.

Cpd. No. 196: ESI-MS [M+H]: 817.42.

Cpd. No. 197: ESI-MS [M+H]: 849.45.

Cpd. No. 198: ESI-MS [M+H]: 861.41.

Cpd. No. 199: ESI-MS [M+H]: 788.50.

Cpd. No. 200: ESI-MS [M+H]: 817.42.

Cpd. No. 201: ESI-MS [M+H]: 831.28.

Cpd. No. 202: ESI-MS [M+H]: 817.29.

Cpd. No. 203: ESI-MS [M+H]: 831.28.

Cpd. No. 204: ESI-MS [M+H]: 831.35.

Cpd. No. 205: ESI-MS [M+H]: 817.27.

Cpd. No. 206: ESI-MS [M+H]: 788.39.

Cpd. No. 207: ESI-MS [M+H]: 774.26.

Cpd. No. 208: ESI-MS [M+H]: 788.31.

Cpd. No. 209: ESI-MS [M+H]: 774.30.

Cpd. No. 301: ESI-MS [M+H]: 817.32.

Cpd. No. 302: ESI-MS [M+H]: 817.36.

Cpd. No. 306: ESI-MS [M+H]: 774.35.

Cpd. No. 311: ESI-MS [M+H]: 788.39.

Cpd. No. 407: 2-chloro-4-((3S)-8-(4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)azetidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 789.34; calcd: 789.33; >95% purity.

Cpd. No. 408: 2-chloro-4-((3S)-8-(4-(7-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)-2-azaspiro[3.5]nonane-2-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 814.33; calcd: 814.35; >95% purity.

Cpd. No. 409: 2-chloro-4-((3S)-8-(4-(6-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)-2-azaspiro[3.3]heptane-2-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 800.35; calcd: 800.33; >95% purity.

Cpd. No. 410: 2-chloro-4-((3S)-8-(4-((1S,4S)-5-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 801.36; calcd: 801.33; >95% purity.

Cpd. No. 411: 2-chloro-4-((3S)-8-(4-((1R,4R)-5-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 801.34; calcd: 801.33; >95% purity.

Cpd. No. 412: 2-chloro-4-((3S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 790.31; calcd: 790.33; >95% purity.

Cpd. No. 413: 2-chloro-4-((3S)-8-(4-(4-(1-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 790.32; calcd: 790.33; >95% purity.

Cpd. No. 414: 5-((3S)-8-(4-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)-3-(trifluoromethyl)picolinonitrile. LC-MS (ESI) m/z (M+H)⁺: 809.35; calcd: 809.34; >95% purity.

Cpd. No. 415: 4-((3S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)-2-(trifluoromethyl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 823.38; calcd: 823.36; >95% purity.

Cpd. No. 416: 2-(difluoromethyl)-4-((3S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 805.36; calcd: 805.37; >95% purity.

Cpd. No. 417: 2-chloro-4-((3S)-8-(6-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)pyridin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 790.35; calcd: 790.33; >95% purity.

Cpd. No. 418: 2-chloro-4-((3S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 789.35; calcd: 789.33; >95% purity.

Cpd. No. 419: 2-chloro-4-((3S)-8-(6-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)pyridazin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 791.34; calcd: 791.32; >95% purity.

Cpd. No. 420: 4-((3S)-8-(4-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)-2-(trifluoromethyl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 808.36; calcd: 808.35; >95% purity.

Cpd. No. 421: 2-(difluoromethyl)-4-((3S)-8-(4-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 790.38; calcd: 790.36; >95% purity.

Cpd. No. 422: 2-chloro-4-((3S)-8-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-1,2,3,5,6,7-hexahydropyrrolo[3,4-f]isoindole-2-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 691.23; calcd: 691.25; >95% purity.

Cpd. No. 423: 4-((3S)-8-(4-(4-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)-2-(trifluoromethyl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 822.38; calcd: 822.36; >95% purity.

Cpd. No. 424: 2-chloro-4-((3S)-8-(5-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)pyridin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 790.35; calcd: 790.33; >95% purity.

Cpd. No. 425: 2-chloro-4-((3S)-8-(6-(4-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)piperidine-1-carbonyl)pyridazin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 790.34; calcd: 790.33; >95% purity.

Cpd. No. 426: 2-chloro-4-((3S)-8-(5-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)piperidine-1-carbonyl)pyridin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 775.32; calcd: 775.31; >95% purity.

Cpd. No. 427: 2-chloro-4-((3S)-8-(5-(4-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)piperidine-1-carbonyl)pyridin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 789.34; calcd: 789.33; >95% purity.

Cpd. No. 428: 2-chloro-4-((3S)-8-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1,2,3,5,6,7-hexahydrocyclopenta[f]isoindol-6-yl)methyl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 788.35; calcd: 788.33; >95% purity.

Cpd. No. 429: 2-chloro-4-((3S)-8-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1,2,3,5,6,7-hexahydrocyclopenta[f]isoindol-6-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 774.34; calcd: 774.32; >95% purity.

Cpd. No. 430: 2-chloro-4-((3S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 788.35; calcd: 788.33; >95% purity.

Cpd. No. 431: 3-(4-(4-((S)-2-(3-chloro-4-cyanophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-8-yl)benzoyl)piperazin-1-yl)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbonitrile. LC-MS (ESI) m/z (M+H)⁺: 814.35; calcd: 814.33; >95% purity.

Cpd. No. 432: 2-chloro-4-((3S)-8-(6-(4-(6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)piperidine-1-carbonyl)pyridazin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 776.32; calcd: 776.31; >95% purity.

Cpd. No. 434: 4-((3S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)-2-fluorobenzonitrile. LC-MS (ESI) m/z (M+H)⁺: 773.38; calcd: 773.36; >95% purity.

Cpd. No. 435: 4-((3S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)-2-fluoro-3-methylbenzonitrile. LC-MS (ESI) m/z (M+H)⁺: 787.36; calcd: 787.38; >95% purity.

Cpd. No. 436: 2-chloro-4-((3S)-8-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1,2,3,5,6,7-hexahydrocyclopenta[f]isoindole-6-carbonyl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile.

Cpd. No. 437: 2-chloro-4-((3S)-8-(4-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-1,2,3,5,6,7-hexahydrocyclopenta[f]isoindol-6-yl)acetyl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile.

Cpd. No. 438: 2-chloro-4-((3S)-8-(4-(4-(2′-(2,6-dioxopiperidin-3-yl)-1′,3′-dioxo-2′,3′,5′,7′-tetrahydro-1′H-spiro[azetidine-3,6′-cyclopenta[f]isoindol]-1-yl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile.

Cpd. No. 439: 2-chloro-4-((3S)-8-(4-(4-((2′-(2,6-dioxopiperidin-3-yl)-1′,3′-dioxo-2′,3′,5′,7′-tetrahydro-1′H-spiro[azetidine-3,6′-cyclopenta[f]isoindol]-1-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile.

Cpd. No. 440: 2-chloro-4-((3S)-8-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3,5,7-tetrahydro-1H-spiro[cyclopenta[f]isoindole-6,4′-piperidin]-1′-yl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile.

Cpd. No. 441: 2-chloro-4-((3S)-8-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3,5,7-tetrahydro-1H-spiro[cyclopenta[f]isoindole-6,4′-piperidin]-1′-yl)methyl)piperidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile.

Cpd. No. 484: 2-chloro-4-((3S)-8-(6-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazine-1-carbonyl)pyridazin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 805.35; calcd: 805.33; >95% purity.

Cpd. No. 485: 2-chloro-4-((3S)-8-(6-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazine-1-carbonyl)pyridazin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 823.34; calcd: 823.32; >95% purity.

Cpd. No. 486: 2-chloro-4-((3S)-8-(5-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazine-1-carbonyl)pyrazin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 800.35; calcd: 823.32; >95% purity.

Cpd. No. 487: 2-chloro-4-((3S)-8-(5-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazine-1-carbonyl)pyrazin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 823.34; calcd: 823.32; >95% purity.

Cpd. No. 488: 2-chloro-4-((3S)-8-(5-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazine-1-carbonyl)pyrazin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 823.35; calcd: 823.33; >95% purity.

Cpd. No. 489: 2-chloro-4-((3S)-8-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1-carbonyl)pyridazin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 833.32; calcd: 833.36; >95% purity.

Cpd. No. 490: 2-chloro-4-((3S)-8-(6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1-carbonyl)pyridazin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 851.32; calcd: 851.35; >95% purity.

Cpd. No. 491: 2-chloro-4-((3S)-8-(6-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-1-carbonyl)pyridazin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 833.40; calcd: 833.36; >95% purity.

Cpd. No. 492: 2-chloro-4-((3S)-8-(5-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1-carbonyl)pyrazin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 833.41; calcd: 833.36; >95% purity.

Cpd. No. 493: 2-chloro-4-((3S)-8-(5-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidine-1-carbonyl)pyrazin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 851.39; calcd: 851.35; >95% purity.

Cpd. No. 494: 2-chloro-4-((3S)-8-(5-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazine-1-carbonyl)pyrazin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 833.32; calcd: 833.36; >95% purity.

Cpd. No. 495: 2-chloro-4-((3S)-8-(5-(4-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)piperidine-1-carbonyl)pyrazin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 790.37; calcd: 790.32; >95% purity.

Cpd. No. 496: 2-chloro-4-((3S)-8-(6-(4-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)piperidine-1-carbonyl)pyridazin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 790.34; calcd: 790.32; >95% purity.

Cpd. No. 497: 2-chloro-4-((3S)-8-(5-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidine-1-carbonyl)pyrazin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 819.37; calcd: 819.34; >95% purity.

Cpd. No. 498: 2-chloro-4-((3S)-8-(5-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidine-1-carbonyl)pyrazin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 837.38; calcd: 837.34; >95% purity.

Cpd. No. 499: 2-chloro-4-((3S)-8-(6-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidine-1-carbonyl)pyridazin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 819.30; calcd: 819.35; >95% purity.

Cpd. No. 500: 2-chloro-4-((3S)-8-(6-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidine-1-carbonyl)pyridazin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 837.38; calcd: 837.34; >95% purity.

Cpd. No. 501: 2-chloro-4-((3S)-8-(6-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)pyridazin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 809.35; calcd: 809.31; >95% purity.

Cpd. No. 502: 2-chloro-4-((3S)-8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 821.38; calcd: 821.34; >95% purity.

Cpd. No. 503: 2-chloro-4-((3S)-8-(6-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazine-1-carbonyl)pyridazin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 823.37; calcd: 823.33; >95% purity.

Cpd. No. 504: 2-chloro-4-((3S)-8-(5-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)pyridin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 808.29; calcd: 808.32; >95% purity.

Cpd. No. 505: 2-chloro-4-((3S)-8-(5-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)pyridin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 808.35; calcd: 808.32; >95% purity.

Cpd. No. 506: 2-chloro-4-((3S)-8-(5-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)pyridin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 808.38; calcd: 808.32; >95% purity.

Cpd. No. 507: 2-chloro-4-((3S)-8-(5-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)pyridin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 808.35; calcd: 808.32; >95% purity.

Cpd. No. 508: 2-chloro-4-((3S)-8-(5-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)pyridin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 818.32; calcd: 818.36; >95% purity.

Cpd. No. 509: 2-chloro-4-((3S)-8-(5-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)pyridin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 818.31; calcd: 818.36; >95% purity.

Cpd. No. 510: 2-chloro-4-((3S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)-2-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 807.38; calcd: 807.32; >95% purity.

Cpd. No. 511: 2-chloro-4-((3S)-8-(4-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidine-1-carbonyl)-2-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 835.39; calcd: 835.35; >95% purity.

Cpd. No. 512: 2-chloro-4-((3S)-8-(5-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)pyrimidin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 791.37; calcd: 791.32; >95% purity.

Cpd. No. 513: 2-chloro-4-((3S)-8-(5-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)pyrimidin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 819.40; calcd: 819.35; >95% purity.

Cpd. No. 514: 2-chloro-4-((3S)-8-(5-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidine-1-carbonyl)pyrimidin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 819.32; calcd: 819.35; >95% purity.

Cpd. No. 515: 2-chloro-4-((3S)-8-(4-((3R)-3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)pyrrolidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 821.37; calcd: 821.34; >95% purity.

Cpd. No. 516: 2-chloro-4-((3S)-8-(4-((3S)-3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)pyrrolidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 803.40; calcd: 803.35; >95% purity.

Cpd. No. 517: 2-chloro-4-((3S)-8-(4-((3R)-3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)pyrrolidine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 821.37; calcd: 821.34; >95% purity.

Cpd. No. 518: 2-chloro-4-((3S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)-2-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 835.39; calcd: 835.35; >95% purity.

Cpd. No. 519: 2-chloro-4-((3S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)-2-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 835.39; calcd: 835.35; >95% purity.

Cpd. No. 520: 2-chloro-4-((3S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)-2-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 835.38; calcd: 835.35; >95% purity.

Cpd. No. 521: 2-chloro-4-((3S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)-2-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 835.31; calcd: 835.35; >95% purity.

Cpd. No. 522: 2-chloro-4-((3S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)-2-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 835.31; calcd: 835.35; >95% purity.

Cpd. No. 523: 2-chloro-4-((3S)-8-(5-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)pyrimidin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 809.37; calcd: 809.31; >95% purity.

Cpd. No. 524: 2-chloro-4-((3S)-8-(5-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazine-1-carbonyl)pyrimidin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 837.31; calcd: 837.34; >95% purity.

Cpd. No. 525: 2-chloro-4-((3S)-8-(5-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)piperidine-1-carbonyl)pyrimidin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 837.37; calcd: 837.34; >95% purity.

Cpd. No. 526: 2-chloro-4-((3S)-8-(5-(4-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)piperidine-1-carbonyl)pyrimidin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 790.38; calcd: 790.33; >95% purity.

Cpd. No. 527: 2-chloro-4-((3S)-8-(4-(4-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)piperidine-1-carbonyl)-2-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 806.37; calcd: 806.33; >95% purity.

Cpd. No. 528: 2-chloro-4-((3S)-8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazine-1-carbonyl)-2-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 821.37; calcd: 821.34; >95% purity.

Cpd. No. 529: 2-chloro-4-((3S)-8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazine-1-carbonyl)-3-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 821.38; calcd: 821.34; >95% purity.

Cpd. No. 530: 2-chloro-4-((3S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)-3-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 825.37; calcd: 825.31; >95% purity.

Cpd. No. 531: 2-chloro-4-((3S)-8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazine-1-carbonyl)-3-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 839.37; calcd: 839.33; >95% purity.

Cpd. No. 532: 2-chloro-4-((3S)-8-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)-2-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 825.35; calcd: 825.31; >95% purity.

Cpd. No. 533: 2-chloro-4-((3S)-8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazine-1-carbonyl)-2-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 839.37; calcd: 839.33; >95% purity.

Cpd. No. 534: 2-chloro-4-((3S)-8-(4-(4-((6-(2,6-dioxopiperidin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)methyl)piperidine-1-carbonyl)-3-fluorophenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 806.37; calcd: 806.33; >95% purity.

Cpd. No. 535: 2-chloro-4-((3S)-8-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)methyl)piperazine-1-carbonyl)phenyl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 803.37; calcd: 803.35; >95% purity.

Cpd. No. 536: 2-chloro-4-((3S)-8-(6-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)piperazine-1-carbonyl)pyridazin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 809.37; calcd: 809.31; >95% purity.

Cpd. No. 537: 2-chloro-4-((3S)-8-(6-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)azetidine-1-carbonyl)pyridazin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 809.35; calcd: 809.31; >95% purity.

Cpd. No. 538: 2-chloro-4-((3S)-8-(6-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)azetidine-1-carbonyl)pyridin-3-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 808.36; calcd: 808.32; >95% purity.

Cpd. No. 539: 2-chloro-4-((3S)-8-(5-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)azetidine-1-carbonyl)pyridin-2-yl)-3-methyl-2,8-diazaspiro[4.5]decan-2-yl)benzonitrile. LC-MS (ESI) m/z (M+H)⁺: 808.38; calcd: 808.32; >95% purity

Example 56

Biological Assays

A. Western Blotting Methods

The appropriate cell line, e.g., prostate cancer LNCaP, Vcap, or 22RV1 cell line, was treated with Compounds of the Disclosure as indicated. The treated cells were lysed with RIPA buffer. The AR level in the cell lysates was examined by western blotting and a specific AR antibody (ab194196, Abcam, Cambridge, Mass. 02139) with concentration of 1:20,000. GAPDH was used as a loading control.

The Western blotting analyses data for representative Compounds of the Disclosure are provided in FIGS. 1-14.

B. Band Quantification and DC₅₀ and DC₉₀ Value Calculation

Bands were quantified with ImageJ software. The relative numbers of each band obtained from normalization with its corresponding GAPDH level were compared with Prism 8 software. The DC₅₀ values were produced from Prism 8, and the DC₉₀ values were calculated with an equation=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((Log EC50−X)*HillSlope) based on DC₅₀ and Hillslope values.

The DC₅₀ and DC₉₀ for Cpd. No. 307 in prostate cancer Vcap cells is 0.046 nM and 0.199 nM, respectively. See FIG. 1.

The DC₅₀ and DC₉₀ for Cpd. No. 293 in prostate cancer Vcap cells is 0.031 nM and 0.41 nM, respectively. See FIG. 2.

The DC₅₀ and DC₉₀ for Cpd. No. 307 in prostate cancer 22RV1 cells is 0.90 nM and 3.1 nM, respectively. See FIG. 3.

The DC₅₀ and DC₉₀ for Cpd. No. 293 in prostate cancer 22RV1 cells is 0.14 nM and 0.23 nM, respectively. See FIG. 4.

The DC₅₀ and DC₉₀ for Cpd. No. 307 in prostate cancer LNCaP cells is 0.082 nM and 0.11 nM, respectively. See FIG. 5.

The DC₅₀ and DC₉₀ for Cpd. No. 293 in prostate cancer LNCaP cells is 0.3 nM and 0.33 nM, respectively. See FIG. 6.

The degradation in Vcap cells of additional representative Compounds of the Disclosure at the concentrations indicated is presented in Table 4.

	TABLE 4
		VCap Cells
	Cpd. No.	10 nM	100 nM
	145	D	C
	146	D	B
	311	A	A
	355	A	A
	356	A	A
	357	A	A
	359	A	A
	360	A	A
	361	A	A
	362	A	A
	363	A	A
	364	A	A
	365	A	A
	366	A	A
	367	A	A
	368	A	A
	369	A	A
	370	A	A
	371	A	A
	372	A	A
	373	A	A
	374	A	A
	375	A	A
	376	A	A
	377	B	A
	378	B	A
	379	A	A
	380	A	A
	381	A	A
	382	A	A
	383	A	A
	384	A	A
	385	A	A
	386	A	A
	387	A	A
	388	A	A
	389	A	A
	390	A	A
	391	A	A
	392	A	A
	393	A	A
	394	A	A
	395	D	C
	396	D	B
	397	C	A
	398	B	A
	399	B	A
	400	A	A
	401	A	A
	402	A	A
	403	A	A
	404	A	A
	405	A	A
	406	D	C
	469	D	B
	470	D	B
	471	B	A
	472	C	A
	473	D	B
	A: >90% degradation (24 hr treatment)
	B: >50% degradation but <90% (24 hr treatment)
	C: >10% degradation but <50% (24 hr treatment)
	D: No significant degradation (24 hr treatment)

The degradation in MDA-MB-453 cells of additional representative Compounds of the Disclosure at the concentrations indicated is presented in Table 5

	TABLE 5
		MDA-MB-453
	Cpd. No.	10 nM	100 nM
	480	B	A
	481	B	A
	482	D	D
	483	D	D
	A: >90% degradation (24 hr treatment)
	B: >50% degradation but <90% (24 hr treatment)
	C: >10% degradation but <50% (24 hr treatment)
	D: No significant degradation (24 hr treatment)

The DC₅₀'s in VCap cells of representative Compounds of the Disclosure are provided in Table 6.

TABLE 6
         VCaP
Cpd. No. DC50 (nM)
484      1-10
485      1-10
486      1-10
487      1-10
488      1-10
489      1-10
490      1-10
491      1-10
492      1-10
493      1-10
494      1-10
495      1-10
496      <1
497      <1
498      1-10
499      <1
500      1-10
501      <1
502      <1
503      1-10
504      <1
505      <1
506      <1
507      10-100
508      <1
509      <1
510      <1
511      <1
512      <1
513      <1
514      <1
515      10-100
516      1-10
517      1-10
518      10-100
519      <1
520      <1
521      <1
522      <1
523      <1
524      <1
525      <1
526      <1
527      <1
528      <1
529      1-10
530      <1
531      1-10
532      <1
533      <1
534      <1
535      <1
536      <1
537      1-10
538      1-10
539      1-10

C. VCaP Xenograft Model in SCID Mice

Xenograft tumors were established by injecting 5×106 VCaP cells in 50% Matrigel subcutaneously on the dorsal side of severe combined immunodeficient (SCID) mice, obtained from Charles River, one tumor per mouse. When tumors reached ˜100 mm³, mice were randomly assigned to treatment and vehicle control groups. Animals were monitored for any signs of toxicity. The antitumor activity of Cpd. No. 307 and Cpd. No. 293 is shown in FIG. 15 and FIG. 16, respectively. The antitumor activity of other representative Compounds of the Disclosure is shown in FIGS. 28-35.

D. Pharmacokinetics in Mice and Rats

The pharmacokinetics of representative Compounds of the Disclosure were determined after oral and IV dosing at the concentrations indicated in mouse (Table 7). These compounds show surprising oral bioavailability and other PK properties. The vehicles used in these studies are either (i) 10% PEG400+90% PBS (adjusted to pH to 8.0 by 0.5 N NaOH); or (ii) 100% PEG200.

TABLE 7
Mouse PK Sudies
	IV					PO
Cpd.	Dose	T1/2	AUC(0 − t)	VSS	Cl	Dose	Tmax	T1/2	Cmax	AUC(0 − t)	F
No.	mg/kg	h	h * ng/mL	L/kg	L/h/kg	mg/kg	h	h	ng/mL	h * ng/mL	%
307	2	4.34	50538	0.23	0.04	5	2.0	4.4	9124	85243	67
311	2	7.22	13968	1.1	0.13	5	4.0	5.01	2819	28708	82
442	1	9.2	5237	1.7	0.17	3	2.67	5.37	847	6572	42
443	1	7.1	8436	1.02	0.12	3	2.0	5.38	1869	15486	67
444	1	8.3	7805	1.2	0.11	3	4.0	6.9	1251	15952	68
445	1	7.4	5176	1.53	0.18	3	3.33	5.37	1131	11895	77
448	1	2.74	78	25.3	12.2	3	1.67	4.78	16	60	26
492	1	3.3	277	7.71	3.27	3	0.5	2.1	59	123	15
493	1	4.9	840	4.12	1.22	3	0.7	4.8	224	627	25
494	1	5.4	180	16.9	5.24	3	0.5	2.4	36	49	9
486	1	2.3	166	9.16	5.85	3	1.0	2.0	44	78	16
487	1	2.1	364	2.65	2.69	3	0.8	1.7	189	353	32
488	1	5.0	233	7.75	4.21	3	1.0	3.1	99.6	213	31
489	1	7.45	2135	2.72	0.44	3	1.0	7.5	477	2393	37
490	1	8.7	4922	1.74	0.18	3	1.0	7.1	639	3729	25
491	1	7.7	2644	2.09	0.36	3	1.0	5.7	789	2709	34
588	1	9.5	1076	6.76	0.83	3	1.0	5.9	347	1759	54
484	1	6.1	7768	0.62	0.12	3	1.3	4.5	2375	10650	46
485	1	9.8	2346	2.95	0.39	3	1.0	7.2	1105	5153	73
496	1	5.8	3031	1.46	0.32	3	1.0	4.1	1419	6548	72
495	1	2.6	950	2.59	0.97	3	0.8	3.4	722	3046	107
497	1	2.7	849	2.0	1.13	3	0.5	2.0	336	760	30
499	1	3.6	1916	1.73	0.49	3	1.3	2.0	404	1668	29
498	1	1.9	419	3.22	2.21	3	0.8	2.3	191	572	45
500	1	2.6	1882	1.53	0.47	3	1.7	2.0	711	3747	60
302	1	7.0	5033	1.45	0.19	3	1.3	7.3	526	4054	27
540	1	7.3	7993	0.96	0.12	3	3.3	7.8	1130	14527	61
344	1	6.9	4926	1.58	0.19	3	4.0	6.0	841	9467	64
346	1	8.8	3030	2.7	0.3	3	3.3	7.2	260	2953	32
348	1	7.5	10113	0.9	0.1	3	2.0	7.6	334	3739	12
502	1	10.0	3487	3.0	0.2	3	3.3	9.5	289	3393	32
521	1	8.2	2988	3.1	0.3	3	1.7	7.0	344	2726	30
522	1	8.6	1723	4.6	0.5	3	2.0	6.0	196	1731	33
529	1	10.2	5131	2.2	0.2	3	3.3	8.5	507	6917	45
528	1	8.9	1712	5.7	0.5	3	1.7	8.8	149	1682	33
510	1	8.3	4078	2.1	0.2	3	2.7	7.2	518	6269	51
511	1	8.0	9040	0.9	0.1	3	2.7	6.4	668	7522	28

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It is to be understood that the foregoing embodiments and exemplifications are not intended to be limiting in any respect to the scope of the disclosure, and that the claims presented herein are intended to encompass all embodiments and exemplifications whether or not explicitly presented herein

All patents and publications cited herein are fully incorporated by reference in their entirety.

Claims

1. A compound of Formula I:

2. The compound of claim 1, wherein E is selected from the group consisting of:

3. The compound of claim 2, wherein E is E-1, or a pharmaceutically acceptable salt or solvate thereof.

4. The compound of claim 3, wherein E-1 is selected from the group consisting of:

5. The compound of claim 4, wherein E-1 is E-1-1, or a pharmaceutically acceptable salt or solvate thereof.

6. The compound of claim 5, wherein R1a and R1b are hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

7. The compound of claim 6, wherein q, r, s, and t are 1, or a pharmaceutically acceptable salt or solvate thereof.

8. The compound of claim 6, wherein q is 2; r is 1; s is 0; and t is 1, or a pharmaceutically acceptable salt or solvate thereof.

9. The compound of claim 6, wherein q is 1; r is 0; s is 0; and t is 2, or a pharmaceutically acceptable salt or solvate thereof.

10. The compound of claim 6, wherein q is 0; r is 1; s is 1; and t is 1, or a pharmaceutically acceptable salt or solvate thereof.

11. The compound of claim 6, wherein q is 1; r is 1; s is 0; and t is 1, or a pharmaceutically acceptable salt or solvate thereof.

12. The compound of claim 5, wherein R1a and R1b are independently C1-C3 alkyl, or a pharmaceutically acceptable salt or solvate thereof.

13. The compound of claim 12, wherein q, r, s, and t are 1, or a pharmaceutically acceptable salt or solvate thereof.

14. The compound of claim 5, wherein R1a is C1-C3 alkyl; and R1b is hydrogen or a pharmaceutically acceptable salt or solvate thereof.

15. The compound of claim 14, wherein q, r, s, and t are 1, or a pharmaceutically acceptable salt or solvate thereof.

16. The compound of claim 15 of Formula III:

17. The compound of claim 15 of Formula IV:

18. The compound of claim 5, wherein R1a and R1b taken together with the carbon atom to which they are attached form an —C(═O)— group, or a pharmaceutically acceptable salt or solvate thereof.

19. The compound of claim 18, wherein q, r, s, and t are 1, or a pharmaceutically acceptable salt or solvate thereof.

20. The compound of claim 4, wherein: E-1 is E-1-2;R1c is C1-C3 alkyl;R1d is selected from the group consisting of hydrogen and C1-C3 alkyl; orR1c and R1d taken together with the carbon atom to which they are attached form an —C(═O)— group,or a pharmaceutically acceptable salt or solvate thereof.

21. The compound of claim 20, wherein R1d is hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

22. The compound of claim 21 of Formula V:

23. The compound of claim 21 of Formula VI:

24. The compound of claim 20, wherein R1c and R1d taken together with the carbon atom to which they are attached form an —C(═O)— group, or a pharmaceutically acceptable salt or solvate thereof.

25. The compound of claim 2, wherein E is E-2, or a pharmaceutically acceptable salt or solvate thereof.

26. The compound of claim 25, wherein E-2 is:

27. The compound of claim 2, wherein E is E-3, or a pharmaceutically acceptable salt or solvate thereof.

28. The compound of claim 27, wherein E-3 is:

29. The compound of any one of claims 1-26, wherein X1 is —C(═O)—, or a pharmaceutically acceptable salt or solvate thereof.

30. The compound of any one of claims 1-26, wherein X1 is —S(═O)2—, or a pharmaceutically acceptable salt or solvate thereof.

31. The compound of any one of claims 1-26, wherein X1 is —CR4aR4b—, or a pharmaceutically acceptable salt or solvate thereof.

32. The compound of claim 31, wherein R4a and R4b are hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

33. The compound of any one of claims 1-28, wherein X1 is absent, or a pharmaceutically acceptable salt or solvate thereof.

34. The compound of any one of claims 1-33, wherein: A1 is selected from the group consisting of:

35. The compound of claim 34, wherein A1 is A1-2, or a pharmaceutically acceptable salt or solvate thereof.

36. The compound of claim 34 or 35, wherein R5a, R5b, R5c, and R5d are hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

37. The compound of any one of claims 1-36, wherein X2 is —C(═O)—, or a pharmaceutically acceptable salt or solvate thereof.

38. The compound of any one of claims 1-36, wherein X2 is —S(═O)2—, or a pharmaceutically acceptable salt or solvate thereof.

39. The compound of any one of claims 1-36, wherein X2 is —O—, or a pharmaceutically acceptable salt or solvate thereof.

40. The compound of any one of claims 1-36, wherein X2 is —CR4cR4d—, or a pharmaceutically acceptable salt or solvate thereof.

41. The compound of claim 40, wherein R4c and R4d are hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

42. The compound of any one of claims 1-36, wherein X2 is absent, or a pharmaceutically acceptable salt or solvate thereof.

43. The compound of claim 1 of Formula VII:

44. The compound of any one of claims 1-43, wherein J1 is cycloalkylenyl, or a pharmaceutically acceptable salt or solvate thereof.

45. The compound of any one of claims 1-43, wherein J1 is heterocyclenyl, or a pharmaceutically acceptable salt or solvate thereof.

46. The compound of claim 45, wherein J1 is selected from the group consisting of:

47. The compound of any one of claims 1-46, wherein J1 is absent, or a pharmaceutically acceptable salt or solvate thereof.

48. The compound of any one of claims 1-42 or 44-47, wherein J2 is selected from the group consisting of —(CH2)m1— and —C≡C—; and m1 is 0, 1, or 2, or a pharmaceutically acceptable salt or solvate thereof.

49. The compound of claim 48, wherein J2 is —(CH2)m1—; and m1 is 0, or a pharmaceutically acceptable salt or solvate thereof.

50. The compound of claim 48, wherein J2 is —(CH2)m1—; and m1 is 1, or a pharmaceutically acceptable salt or solvate thereof.

51. The compound of claim 48, wherein J2 is —C≡C—, or a pharmaceutically acceptable salt or solvate thereof.

52. The compound of any one of claims 1-42 or 44-51, wherein J3 is selected from the group consisting of cycloalkylenyl and heterocyclenyl, or a pharmaceutically acceptable salt or solvate thereof.

53. The compound of any one of claims 1-42 or 44-51, wherein J3 is absent, or a pharmaceutically acceptable salt or solvate thereof.

54. The compound of any one of claims 1-53, wherein J4 is selected from the group consisting of alkylenyl, cycloalkylenyl, and heterocyclenyl, or a pharmaceutically acceptable salt or solvate thereof.

55. The compound of any one of claims 1-54, wherein J4 is absent, or a pharmaceutically acceptable salt or solvate thereof.

56. The compound of any one of claims 1-55, wherein: J5 is selected from the group consisting of —O— and —N(H)—; andB1 is selected from the group consisting of B1-1, B1-2, B1-3, B1-4, B1-15, B1-16, B1-17, B1-18, B1-19, B1-20, B1-21, B1-22, B1-23, B1-24, B1-25, and B1-26, or a pharmaceutically acceptable salt or solvate thereof.

57. The compound of any one of claims 1-54, wherein: J5 is selected from the group consisting of —(CH2)m2— and —O—;m2 is 0;J4 is selected from the group consisting of:

58. The compound of claim 56 or 57, wherein B1 is B1-1, or a pharmaceutically acceptable salt or solvate thereof.

59. The compound of claim 58, wherein Z is —CH2—, or a pharmaceutically acceptable salt or solvate thereof.

60. The compound of claim 58, wherein Z is —C(═O)—, or a pharmaceutically acceptable salt or solvate thereof.

61. The compound of claim 56 or 57, wherein B1 is B1-2, or a pharmaceutically acceptable salt or solvate thereof.

62. The compound of claim 61, wherein Z is —CH2—, or a pharmaceutically acceptable salt or solvate thereof.

63. The compound of claim 61, wherein Z is —C(═O)—, or a pharmaceutically acceptable salt or solvate thereof.

64. The compound of claim 56 or 57, wherein B1 is B1-3, or a pharmaceutically acceptable salt or solvate thereof.

65. The compound of claim 56 or 57, wherein B1 is B1-4, or a pharmaceutically acceptable salt or solvate thereof.

66. The compound of any one of claims 56-65, wherein R2a, R2b, and R2c are independently selected from the group consisting of hydrogen and fluoro, or a pharmaceutically acceptable salt or solvate thereof.

67. The compound of 66, wherein R2a, R2b, and R2c are hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

68. The compound of any one of claims 1-55, wherein: J5 is selected from the group consisting of —(CH2)m2— and —C(═O)—;m2 is 0, 1, 2, or 3; andB1 is selected from the group consisting of B1-5, B1-6, B1-7, B1-27, and B1-28, or a pharmaceutically acceptable salt or solvate thereof.

69. The compound of claim 68, wherein B1 is B1-5, or a pharmaceutically acceptable salt or solvate thereof.

70. The compound of claim 68, wherein Z is —CH2—, or a pharmaceutically acceptable salt or solvate thereof.

71. The compound of claim 68 wherein Z is —C(═O)—, or a pharmaceutically acceptable salt or solvate thereof.

72. The compound of any one of claims 69-71, wherein m is 1 or 2; and n is 1, or a pharmaceutically acceptable salt or solvate thereof.

73. The compound of claim 68, wherein B1 is B1-6, or a pharmaceutically acceptable salt or solvate thereof.

74. The compound of claim 73, wherein Z is —CH2—, or a pharmaceutically acceptable salt or solvate thereof.

75. The compound of claim 73, wherein Z is —C(═O)—, or a pharmaceutically acceptable salt or solvate thereof.

76. The compound of any one of claims 73-75, wherein m is 1 or 2; and n is 1 or 2, or a pharmaceutically acceptable salt or solvate thereof.

77. The compound of claim 68, wherein B1 is B1-7, or a pharmaceutically acceptable salt or solvate thereof.

78. The compound of claim 77, wherein m is 1 or 2; and n is 1 or 2, or a pharmaceutically acceptable salt or solvate thereof.

79. The compound any one of claims 1-54, wherein: J5 is selected from the group consisting of —(CH2)m2— and —C(═O)—;m2 is 0, 1, 2, or 3; andB1 is selected from the group consisting of B1-9, B1-10, and B1-11,or a pharmaceutically acceptable salt or solvate thereof.

80. The compound of claim 79, wherein B1 is B1-9, or a pharmaceutically acceptable salt or solvate thereof.

81. The compound of claim 79, wherein B1 is B1-10, or a pharmaceutically acceptable salt or solvate thereof.

82. The compound of claim 79, wherein B1 is B1-11, or a pharmaceutically acceptable salt or solvate thereof.

83. The compound of any one of claims 79-82, wherein o is 1 or 2; and p is 1 or 2, or a pharmaceutically acceptable salt or solvate thereof.

84. The compound any one of claims 1-54, wherein: J5 is selected from the group consisting of —(CH2)m2— and —C(═O)—;m2 is 0, 1, 2, or 3; andB1 is selected from the group consisting of B1-12, B1-13, and B1-14,or a pharmaceutically acceptable salt or solvate thereof.

85. The compound of claim 84, wherein B1 is B1-12, or a pharmaceutically acceptable salt or solvate thereof.

86. The compound of claim 84, wherein B1 is B1-13, or a pharmaceutically acceptable salt or solvate thereof.

87. The compound of claim 84, wherein B1 is B1-14, or a pharmaceutically acceptable salt or solvate thereof.

88. The compound of any one of claims 79-87, wherein m is 1 or 2; and n is 1, or a pharmaceutically acceptable salt or solvate thereof.

89. The compound of any one of claims 79-81, 83-86, or 88, wherein Z is —CH2—, or a pharmaceutically acceptable salt or solvate thereof.

90. The compound of any one of claims 79-81, 83-86, or 88, wherein Z is —C(═O)—, or a pharmaceutically acceptable salt or solvate thereof.

91. The compound of any one of claims 68-90, wherein R2d and R2e are independently selected from the group consisting of hydrogen and fluoro, or a pharmaceutically acceptable salt or solvate thereof.

92. The compound of any one of claims 56-91, wherein R3 is hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

93. The compound of any one of claims 1-55, wherein B1 is selected from the group consisting of:

94. The compound of claim 93, wherein B1 is:

95. The compound of claim 93, wherein B1 is:

96. The compound of any one of claims 1-92, wherein R8 is hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

97. The compound of any one of claims 1-96, wherein R3a is halo, or a pharmaceutically acceptable salt or solvate thereof.

98. The compound of any one of claims 1-96, wherein R3a is C1-C4 alkyl, or a pharmaceutically acceptable salt or solvate thereof.

99. The compound of any one of claims 1-96, wherein R3a is C1-C4 haloalkyl, or a pharmaceutically acceptable salt or solvate thereof.

100. The compound of any one of claims 1-96, wherein R3a is selected from the group consisting of —Cl, —CH3, and —CF3, or a pharmaceutically acceptable salt or solvate thereof.

101. The compound of any one of claims 1-100, wherein Z1 is —C(H)═, or a pharmaceutically acceptable salt or solvate thereof.

102. The compound of any one of claims 1-101, wherein Z2 is —C(H)═, or a pharmaceutically acceptable salt or solvate thereof.

103. The compound of claim 1 of Formula VIII:

104. The compound of claim 34 of Formula XV:

105. The compound of claim 104, or a pharmaceutically acceptable salt or solvate thereof, wherein B1 is selected from the group consisting of:

106. The compound of claim 34 of Formula XVI:

107. The compound of claim 106, or a pharmaceutically acceptable salt or solvate thereof, wherein B1 is selected from the group consisting of:

108. The compound of claim 1 selected from any one or more of the compounds of Table 1, or a pharmaceutically acceptable salt or solvate thereof.

109. A pharmaceutical composition comprising the compound of any one of claims 1-108, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

110. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-108, or a pharmaceutically acceptable salt or solvate thereof.

111. The method of claim 110, wherein the cancer is breast cancer or prostate cancer.

112. The pharmaceutical composition of claim 109 for use in treating cancer.

113. The pharmaceutical composition of claim 112, wherein the cancer is breast cancer or prostate cancer.

114. A compound of any one of claims 1-108, or a pharmaceutically acceptable salt or solvate thereof, for use in treating of cancer.

115. The compound for use of claim 114, wherein the cancer is breast cancer or prostate cancer.

116. Use of a compound of any one of claims 1-108, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for treatment of cancer.

117. The use of claim 116, wherein the cancer is breast cancer or prostate cancer.

118. A method of reducing androgen receptor protein within a cell of a patient in need thereof, the method comprising administering to the subject a compound of any one of claims 1-108, or a pharmaceutically acceptable salt or solvate thereof.

119. A kit comprising the compound of any one of claims 1-108, or a pharmaceutically acceptable salt or solvate thereof, and instructions for administering the compound, or a pharmaceutically acceptable salt or solvate thereof, to a subject having cancer.

120. A compound of Formula II: