Bifunctional compounds for degrading BTK via the ubiquitin proteosome pathway

Abstract

To provide bifunctional compounds for degrading BTK via a ubiquitin proteasome pathway.SOLUTION: The present invention relates to compounds useful for degrading BTK via a ubiquitin proteolytic pathway. The invention also provides pharmaceutically acceptable compositions comprising the compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This PCT application claims the benefit of U.S. Provisional Patent Application No. 62 / 745,786, filed October 15, 2018; U.S. Provisional Patent Application No. 62 / 767,819, filed November 15, 2018; U.S. Provisional Patent Application No. 62 / 836,398, filed April 19, 2019; U.S. Provisional Patent Application No. 62 / 887,812, filed August 16, 2019; and U.S. Provisional Patent Application No. 62 / 901,984, filed September 18, 2019. Each of these documents is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION The present invention provides novel bifunctional compounds for proteolyzing the target Bruton's tyrosine kinase (BTK) and methods for treating diseases regulated by BTK. [Background technology]

[0003] background

[0003] B cell receptor (BCR) signaling regulates B cell development and the activation, signaling, and survival of mature B cells. Misregulation of the BCR signaling pathway is associated with numerous disease manifestations involving B cell function, and targeting B cells and BCR signaling has clear therapeutic potential (Woyach, et al.; Blood. 120(6); 1175-1184. 2012). For example, depletion of B cells with monoclonal antibodies targeting CD20 has significant effects in the treatment of B cell malignancies and autoimmune and inflammatory diseases (Cang, et al.; J Hematolo Oncol. 5; 64, 2012).

[0004] BTK is a member of the TEC family of kinases and a crucial signaling hub in the BCR pathway. Mutations in BTK cause X-linked agammaglobulinemia (XLA), in which B cell maturation is impaired, resulting in reduced immunoglobulin production (Hendriks, et al.; Expert Opin Ther Targets 15; 1002-1021, 2011). BTK's central role in B cell signaling and function makes it an attractive therapeutic target for B cell malignancies and autoimmune and inflammatory diseases. Ibrutinib, a covalent inhibitor of BTK, has been approved for the treatment of chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and other B cell malignancies, as well as graft-versus-host disease (GvHD) (Miklos, et al.; Blood. 120(21); 2243-2250, 2017). Ibrutinib and second-generation BTK inhibitors are currently being investigated for oncology and immune-related indications, such as rheumatoid arthritis (Akinleye, et al.; J of Hematolo Oncol. 6: 59, 2013; Liu, et al.; J Pharm and Exper Ther. 338(1): 154-163. 2011; Di Paolo, et al.; Nat Chem Biol. 7(1): 41-50. 2011).

[0005] As an alternative to stoichiometric inhibition, proteolysis of BTK can have dramatic consequences on B cell function by effectively blocking BCR signaling. Ablation of the BTK protein can eliminate BTK kinase activity as well as any protein interaction or scaffolding function of BTK. Specific degradation of BTK can be achieved by using heterobifunctional small molecules to recruit BTK to ubiquitin ligase, thereby promoting BTK ubiquitination and proteasomal degradation. Thalidomide derivatives, such as lenalidomide or pomalidomide, can be used to recruit potential substrates to cereblon (CRBN), a component of the ubiquitin ligase complex. This unique therapeutic approach utilizes chemical This may offer a mechanism of action for disrupting BTK activity and BCR signaling that is distinct from that of stoichiometric BTK inhibition. Furthermore, this degradation approach may effectively target the BTKC481S mutation, which has been observed clinically and confers resistance to ibrutinib inhibition (Woyach, et al.; Blood. 120(6): 1175-1184. 2012). Summary of the Invention [Problem to be solved by the invention]

[0006]

[0006] Currently, there remains a need for bifunctional molecules that can induce the proteolysis of BTK via the ubiquitin proteolytic pathway. [Means for solving the problem]

[0007] Summary of the Invention

[0007] The present invention provides bifunctional compounds that induce the proteolysis of BTK via the ubiquitin proteolytic pathway.

[0008] The present invention relates to a compound of formula (A): [ka] or a pharmaceutically acceptable salt thereof, wherein W is CH or N; D is a bond or -NH-; ring A is phenyl, a 9-10 membered bicyclic aryl, a 5-6 membered partially or fully unsaturated monocyclic heterocycle, or a 9-10 membered bicyclic heteroaryl, wherein the monocyclic heterocycle and bicyclic heteroaryl of ring A each have 1-3 heteroatoms independently selected from N, O, or S, and ring A is optionally and independently selected from halo, -CN, -COOH, NH, and optionally substituted C 1~6 Ring B is substituted by up to three substituents selected from phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, or 8-10 membered (e.g., 8-9 membered or 9-10 membered) spiro bicyclic heterocycle, Ring B is optionally substituted, and the heteroaryl and heterocycloalkyl of Ring B have 1-3 heteroatoms independently selected from N, O, or S; L is -X 1 -X 2 -X 3 -X 4 -X 5 -and;X 1 is a bond, -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 a 7- to 12-membered spiro or fused bicyclic heterocycloalkyl having 1 to 3 heteroatoms independently selected from alkyl-, N, O, or S, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; and X 1 Each of the monocyclic and bicyclic heterocycloalkyl groups is optionally substituted by —CH3; 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5alkyl-, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~8 Alkyl-, -C≡C-, 4-6 membered cycloalkyl, -N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) p -, -(CH2-CH 2-O) p a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from -, N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH; 4 is a bond, -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-, -(O-CH2-CH2-CH2) m -, a 5- to 6-membered saturated, partially unsaturated, or fully unsaturated carbocyclic ring, or a 5- to 6-membered saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from N, O, or S; X 5 is a bond, -C 1~4 alkyl-, -N(R)-, -O-, -C(O)-, or -C(O)-N(R)-; each R is independently -H or -C 1~3 alkyl; and each of m, n, and p is independently an integer from 1 to 3 (e.g., 1, 2, or 3); and Y is [ka] where each R 2 are independently halo, -CN, or C 1~4 is alkyl, where So, each C 1~4 alkyl is optionally and independently substituted with up to three of halo, —CN, —COOH, —COONH2, —NH2, or —CF3; each R″ and R′′ is independently H or, together with the atom to which they are attached, forms a 5-6 membered partially or fully unsaturated benzo-fused heterocyclic ring; each Z is —C(R A)2- or -C(O)-; each R A are independently -H or C 1~4 and q is 0, 1, or 2.

[0009] In some embodiments, Ring B is an optionally substituted 5-6 membered heterocycloalkyl having 1-2 nitrogen atoms.

[0010] In some embodiments, Ring B is an optionally substituted 5-6 membered heteroaryl having 1-2 heteroatoms independently selected from N and S.

[0011] In some embodiments, Ring B is: [ka] where R 10 teeth, [ka] and R 1 is C 1~4 For example, ring B is an alkyl group. [ka] where R 10 teeth, [ka] And in one example, ring B is [ka] In another example, R 10 teeth, [ka] is.

[0012] In some embodiments, ring A is [ka] wherein ring A' together with the phenyl ring to which it is fused forms a 9-10 membered bicyclic aryl or a 9-10 membered bicyclic heteroaryl, wherein the bicyclic heteroaryl (i.e., the bicyclic heteroaryl containing ring A') has 1-3 heteroatoms independently selected from N, O, or S. For example, ring A can be [ka] is.

[0013] In some embodiments, X 1 , X 2 , and X 5 At least one of is —N(R)—, —C(O)—N(R)—, or —CH2—.

[0014] In some embodiments, X 1 is -C(O)-N(R)-.

[0015] In some embodiments, X 2 is -(O-CH2-CH2) n -, -(CH2-CH2-O) n - or -C 1~5 It is alkyl-.

[0016] In some embodiments, X 3 is a bond, -C≡C-, -C 1~4 It is alkyl- or -N(R)-.

[0017] In some embodiments, X 4 is a bond, —CH—, or —N(R)—.

[0018] In some embodiments, X 5 is a bond.

[0019] In some embodiments, X 1 -(O-CH2-CH2-CH2) m -, m is 1, and X 2 is -C(O)-N(R)-.

[0020] In some embodiments, X 1 -CH2-, -C(O)-, [ka] is.

[0021] In some embodiments, X 2 is a bond, -C(O)-, -C 1~5 Alkyl-, [ka] is.

[0022] In some embodiments, X 3 is a bond, -C 1~4 alkyl-, 4- to 6-membered cycloalkyl, or -N(R)-.

[0023] In some embodiments, X 3 is a bond, -C 1~4 Alkyl-, -NH-, [ka] Or -C≡C-.

[0024] In some embodiments, X 4 is a bond, [ka] -C1~4 alkyl-, -CH2-CH2-N(R)-, or -N(R)-.

[0025] In some embodiments, X 5 is a bond, -C 1~4 alkyl-, -N(R)-, or -C(O)-N(R)-.

[0026] In some embodiments, L is [ka] [ka] [ka] [ka] [ka] is.

[0027] In some embodiments, Y is [ka] is.

[0028] In some embodiments, W is N.

[0029] In some embodiments, D is a bond.

[0030]

[0030] The present invention also provides a compound represented by formula (B): [ka] or a pharmaceutically acceptable salt thereof, wherein W is CH or N; D is a bond or -NH-; Ring B1 is a 4-6 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic heterocycle or an 8-10 membered fully saturated spiro bicyclic heterocycle, wherein Ring B1 has 1-3 heteroatoms independently selected from N, O, or S and is optionally substituted by 1-3 groups selected from halo, -CH3, -CF3, -C(O)OH, -CH2OH, or a 5-membered heterocycloalkyl (optionally substituted by oxo and having 1-2 heteroatoms independently selected from N or O); L is -X 1 -X 2 -X 3 -and;X 1 is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 a 7- to 12-membered spiro or fused bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, or a 4- to 6-membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein X 1 Each of the monocyclic and bicyclic heterocycloalkyl groups is optionally substituted by —CH3; 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4 Alkyl-, -C≡C-, 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) pa 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms independently selected from -, N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH; each R is independently -H or -C 1~3 alkyl; m, n, and p are each independently an integer from 1 to 3; and Y is [ka] is.

[0031] In some embodiments, Ring B1 is: [ka] and ring B1 is —CH3, —CH2OH, —C(O)OH, —CF3, —F, [ka] For example, ring B1 is optionally substituted with 1 to 3 groups selected from: [ka] In another example, ring B1 is [ka] is.

[0032] In some embodiments, X 1 teeth, [ka] is.

[0033] In some embodiments, X 2 is a bond, -C 1~5 alkyl-, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S. For example, X2 is a bond, -C 1~3 Alkyl-, -C(O)-, [ka] is.

[0034] In some embodiments, X 3 is a bond, -C 1~4 Alkyl-, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p - or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH3. For example, X 3 is a bond, [ka] is.

[0035] In some embodiments, L is [ka] is.

[0036] In some embodiments, W is N and D is a bond.

[0037]

[0037] The present invention also provides a compound represented by formula (C): [ka] or a pharmaceutically acceptable salt thereof, wherein W is CH or N; ring C is phenyl or a saturated, partially unsaturated, or fully unsaturated 5-6 membered monocyclic heterocycle having 1-2 heteroatoms independently selected from N, O, or S, wherein each of the phenyl and heterocycle of ring C is optionally substituted; and L is -X 1 -X 2 -X3 -and;X 1 is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O-(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 alkyl-, a 7-12 membered spiro bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from N, O, or S, or a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein X 1 each of the bicyclic heterocycloalkyl and monocyclic heterocycloalkyl of is optionally substituted by —CH3; 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4 Alkyl -, -C≡C-, 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p a 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms independently selected from -, N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH; each R is independently -H or -C 1~3 alkyl; and m, n, and p are each independently an integer from 1 to 3.

[0038] In some embodiments, ring C is [ka] For example, ring C is [ka] is.

[0039] In some embodiments, X 1 is a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S. For example, X 1 teeth, [ka] is.

[0040] In some embodiments, X 2 is a bond, -C 1~5 alkyl-, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S. For example, X 2 is a bond or -C 1~3 It is alkyl-.

[0041] In some embodiments, X 3 is a 4- to 6-membered cycloalkyl, -N(R)-, or a 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is substituted by -CH3 For example, X 3 teeth, [ka] is.

[0042] In some embodiments, L is [ka] is.

[0043]

[0043] The present invention also provides a compound represented by formula (D) [ka] or a pharmaceutically acceptable salt thereof, wherein W is CH or N; and ring A is [ka] and L is -X 1 -X 2 -X 3 -and;X 1 -C 1~5 alkyl- or a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, where X 1 is optionally substituted by —CH3; 2 is a bond, -C 1~5 alkyl- or a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, where X 1 is optionally substituted by —CH3; 3 is a bond, -C 1~4 alkyl-, a 4-6 membered monocyclic cycloalkyl, or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH3; Y is [ka] and R 10 is halo, -H, -C 1~5 Alkyl, -3 to 6-membered cycloalkyl, 5 to 6-membered heterocycloalkyl, -CN, -OH, -CF3, -CH2OH, -CH2CH2OH, [ka] is.

[0044]

[0044] The present invention also provides a compound represented by formula (D-1) [ka] or a pharmaceutically acceptable salt thereof, wherein W is CH or N; and ring A is [ka] and; L is -X 1 -X 2 -X 3 -and;X 1 -C 1~5 alkyl- or a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, where X 1 is optionally substituted by —CH3; 2 is a bond, -C 1~5 alkyl- or a 4- to 6-membered monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from N, O, or S; chloroalkyl, where X 1 is optionally substituted by —CH3; 3 is a bond, -C 1~4 alkyl-, a 4-6 membered monocyclic cycloalkyl, or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH3; Y is [ka] and R 10 teeth, [ka] is.

[0045] In some embodiments, the compound of formula (D) has the formula (D-2): [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, L, Y, and R 10 The term is as defined in the compounds of formula (A), (B), (C), (D), and (D-1).

[0046] In some embodiments, ring A is [ka] is.

[0047] In some embodiments, X 1 is a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, where X 1 The monocyclic heterocycloalkyl of the formula: is optionally substituted by —CH3. For example, X 1 teeth, [ka] is.

[0048] In some embodiments, X 2 is a bond, -C 1~5 alkyl-, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S. For example, X 2 is a bond or -C 1~4 It is alkyl-.

[0049] In some embodiments, X 3 is a bond, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S. For example, X 3 teeth, [ka] is.

[0050] In some embodiments, L is [ka] is.

[0051] In some embodiments, R 10 teeth, [ka] is.

[0052] In some embodiments, R 10 teeth, [ka] is.

[0053]

[0053] The present invention also provides a compound represented by formula (E): [ka] or a pharmaceutically acceptable salt thereof, wherein D is a bond or —NH—; W is N or CH; ring A is phenyl, a 9-10 membered bicyclic aryl, a 5-6 membered partially or fully unsaturated monocyclic heterocycle, or a 9-10 membered bicyclic heteroaryl, wherein the monocyclic heterocycle and bicyclic heteroaryl of ring A each have 1-3 heteroatoms independently selected from N, O, or S; ring B is an optionally substituted 5-6 membered saturated, partially unsaturated, or fully unsaturated monocyclic heterocycle, or an optionally substituted 8-10 membered (e.g., 8-9 membered or 9-10 membered) spiro bicyclic heterocycle, wherein ring B has 1-3 heteroatoms independently selected from N, O, or S; L is -X 1 -X 2 -X 3 -X 4 -X 5 -and;X 1 is a bond, -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2)m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 alkyl-, a 7-12 membered spiro bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from N, O, or S, or a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein X 1 Each of the monocyclic and bicyclic heterocycloalkyl groups is optionally substituted by —CH3; 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4 Alkyl-, -C≡C-, 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from -, N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH; 4 is a bond, -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-, -(O-CH2-CH2-CH2) m -, a 5- to 6-membered saturated, partially unsaturated, or fully unsaturated carbocyclic ring, or a 5- to 6-membered saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from N, O, or S; X 5 is a bond, —N(R)—, or —C(O)—N(R)—; each R is independently —H or —C 1~3 alkyl; m, n, and p are each independently an integer from 1 to 3 (e.g., 1, 2, or 3); and Y is [ka] where X 1 , X 2 , X 3 , X 4 , and X 5 at least one of which has a nitrogen atom, and Y is X 1 , X 2 , X 3 , X 4 , or X 5 is directly bonded to L at the nitrogen atom of

[0054] In some embodiments, ring B is: [ka] where R 10 teeth, [ka] and R 1 is C 1~4 For example, ring B is an alkyl group. [ka] where R 10 teeth, [ka] In another example, ring B is [ka] is.

[0055] In some embodiments, R 10 teeth, [ka] is.

[0056] In some embodiments, ring A is [ka] is.

[0057] In some embodiments, X 5 is -N(R)-.

[0058] In some embodiments, X 5 is -C(O)-N(R)-.

[0059] In some embodiments, X 5 is a bond.

[0060] In some embodiments, L is [ka] [ka] [ka] [ka] is.

[0061] In some embodiments, Y is [ka] is.

[0062]

[0062] The present invention also provides a compound represented by formula (F) [ka] or a pharmaceutically acceptable salt thereof, wherein W is CH or N; and L is -X 1 -X 2 -X 3 -and;X 1is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 alkyl-, a 7-12 membered spiro bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from N, O, or S, or a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein X 1 Each of the monocyclic and bicyclic heterocycloalkyl groups is optionally substituted by —CH3; 2 is a bond, -C 1~5 Alkyl-, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4 Alkyl-, -C≡C-, 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p independently selected from -, N, O, or S a 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms, wherein the heterocycloalkyl is optionally substituted with —CH3; each R is independently —H or —C 1~3 alkyl; m, n, and p are each independently an integer from 1 to 3; and Y is [ka] is.

[0063] In some embodiments, W is N.

[0064] In some embodiments, Y is [ka] is.

[0065] In some embodiments, X 1 is a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, where X 1 Each monocyclic heterocycloalkyl of is optionally substituted by -CH3. For example, X 1 teeth, [ka] In one example, X 1 teeth, [ka] is.

[0066] In some embodiments, X 2 is a bond or -C 1~5 It is alkyl-.

[0067] In some embodiments, X 3 is a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S. For example, X 3 teeth, [ka] In one example, X 3 teeth, [ka] is.

[0068] In some embodiments, L is [ka] is.

[0069]

[0069] The present invention also provides a compound represented by formula (G): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , L, and Y are as defined for compounds of formula (A), (B), (C), (D), (E), (F), (X), and (I).

[0070] In some embodiments, R 1 is methyl.

[0071] In some embodiments, Y is [ka] is.

[0072] In some embodiments, W is N.

[0073]

[0073] The present invention also provides a compound represented by formula (H) [ka] or a pharmaceutically acceptable salt thereof, wherein ring B, R 2 , Z, W, D, and q are as defined in compounds of formula (A), (B), (C), (D), (E), (F), (G), (X), and (I).

[0074] In some embodiments, q is 0.

[0075]

[0075] The present invention also provides a compound represented by formula (J): [ka] or a pharmaceutically acceptable salt thereof, wherein the rings B, D, W, R 2 , q, and L are as defined in compounds of formula (A), (B), (C), (D), (E), (F), (H), (X), and (I).

[0076]

[0076] The present invention also provides a compound represented by formula (K): [ka] or a pharmaceutically acceptable salt thereof, wherein ring A is [ka] wherein ring A is optionally and independently selected from halo, CN, carboxyl, NH, and optionally substituted C 1~6 and each of E and G is independently 5-6 membered heterocycloalkyl, wherein each heterocycloalkyl contains at least one nitrogen atom. 2 , q, R", R"', and ring A' are as defined in the compound of formula (A).

[0077] In some embodiments, D is a bond and W is a nitrogen atom.

[0078]

[0078] The present invention also provides a compound represented by formula (M) [ka] or a pharmaceutically acceptable salt thereof, wherein R 10A is -H, [ka] where R 1 is C 1~4 is alkyl; X 1 -C 1~5alkyl-; Ring C-1 is a 5- to 6-membered heterocycloalkyl having one nitrogen atom; and Y is [ka] is.

[0079] In some embodiments, R 10A is -H or [ka] is.

[0080] In some embodiments, R 10A teeth, [ka] and R 1 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or isobutyl. For example, R 1 is methyl.

[0081] In some embodiments, X 1 is methylene, ethylene, or propylene. For example, X 1 is methylene.

[0082] In some embodiments, ring C-1 is [ka] For example, ring C-1 is [ka] is.

[0083]

[0083] The present invention also provides a compound represented by formula (X) [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1~3 alkyl; ring A is phenyl, a 5- to 6-membered partially or fully unsaturated monocyclic heterocycle, a 9- to 10-membered bicyclic aryl, or a 9- to 10-membered bicyclic heteroaryl, wherein the heterocycle and bicyclic heteroaryl of ring A each independently have 1 to 3 heteroatoms independently selected from N, O, or S; L is -X 1 -X 2 -X 3 -X 4 -X 5 -and;X 1 is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 7-12 membered spiro bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O, or S (wherein X 1 optionally substituted by —CH3), or a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S (wherein X 1 wherein the monocyclic heterocycloalkyl is optionally substituted by —CH3; 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4 Alkyl-, -C≡C-, 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) pa 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from -, N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH; 4 is a bond, -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-, -(O-CH2-CH2-CH2) m -, a 5- to 6-membered saturated, partially unsaturated, or fully unsaturated carbocyclic ring, or a 5- to 6-membered saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from N, O, or S; X 5 is a bond, -C 1~4 alkyl-, -N(R)-, or -C(O)-N(R)-; each R is independently -H or -C 1~3 alkyl; m, n, and p are each independently an integer from 1 to 3; Y is [ka] where each R 2 are independently halo or C 1~4 alkyl; each Z is -C(R A )2- or -C(O)-; each R A are independently -H or C 1~4 and q is 0, 1, or 2.

[0084] In some embodiments, q is 0. In other embodiments, q is 1 and R 2 is -F.

[0085] In some embodiments, Z is —CH— or —C(O)—.

[0086] In some embodiments, Y is [ka] In some embodiments, Y is [ka] is.

[0087] In some embodiments, R 1 is methyl, ethyl, or propyl. For example, R 1 is methyl.

[0088] In some embodiments, each R is independently -H or -CH3.

[0089] In some embodiments, ring A is [ka] For example, ring A is selected from [ka] is selected from.

[0090] In some embodiments, X 1 , X 2 , and X 5 At least one of is —C(O)—N(R)— or —CH2—.

[0091] In some embodiments, X 1 is -C(O)-N(R)-. In another example, X 1 -C 1~5 alkyl-; 1 independently selected from N, O, or S and a 7- to 12-membered spiro bicyclic heterocycloalkyl having up to 3 heteroatoms, where the heterocycloalkyl is optionally substituted with —CH; or a 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S, where the heterocycloalkyl is optionally substituted with —CH. In some examples, X 1 -CH2-, -C(O)-, [ka] is.

[0092] In some embodiments, X 2 is -(O-CH2-CH2) n -, -(CH2-CH2-O) n - or -C 1~5 In another embodiment, X is alkyl-. 2 is a bond, -C(O)-, -C 1~5 Alkyl-, [ka] For example, X 2 is a bond, -CH2-, -CH2-CH2-, or -CH2-CH2-CH2-.

[0093] In some embodiments, X 3 is a bond, -C≡C-, -C 1~4 alkyl-, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, where the heterocycloalkyl is optionally substituted with —CH3, or —N(R)—. In some examples, X 3 is a bond, -C 1~4 In another embodiment, X is alkyl- or -N(R)-. 3 teeth, [ka] is.

[0094] In some embodiments, X 4 is a bond, -C 1~4 Alkyl-, -(O-CH2-CH2-CH2) m -, or a 5-6 membered saturated, partially unsaturated, or fully unsaturated carbocyclic ring having 0-3 heteroatoms independently selected from N, O, or S. For example, X 4 is a bond, [ka] -C 1~4 In another example, X is alkyl-, -CH-CH-N(R)-, or -N(R)-. 4 is a bond, —CH—, or —N(R)—.

[0095] In some embodiments, X 5 is a bond, -C 1~4 alkyl-, -N(R)-, or -C(O)-N(R)-. For example, X 5 is a bond.

[0096] In some embodiments, X 1 is -(O-CH2-CH2-CH2) m -, m is 1, and X 2 is -C(O)-N(R)-.

[0097] In some embodiments, L is [ka] [ka] [ka] [ka] is.

[0098] Another aspect of the present invention is a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1~3alkyl; ring A is phenyl, a 9-10 membered bicyclic aryl, or a 9-10 membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from N, O, or S; L is -X 1 -X 2 -X 3 -X 4 -X 5 -and;X 1 is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 a 7-12 membered spiro bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, wherein the heterocycloalkyl is optionally substituted with —CH3, or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with —CH3; X 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, 4- to 6-membered cycloalkyl, or 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4 Alkyl-, 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from -, N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH; 4 is a bond, -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-, -(O-CH2-CH2-CH2) m- or a 5- to 6-membered saturated, partially unsaturated, or fully unsaturated heterocycle having 1 to 3 heteroatoms independently selected from N, O, or S; X 5 is a bond, -C 1~4 alkyl-, -N(R)-, or -C(O)-N(R)-; each R is independently -H or -C 1~3 alkyl; m, n, and p are each independently an integer from 1 to 3; Y is [ka] where each R 2 are independently halo or C 1~4 alkyl; each Z is -C(R A )2- or -C(O)-; each R A are independently -H or C 1~4 and q is 0, 1, or 2.

[0099] In some embodiments, the compound of formula (I) has the formula (IA): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1~3 alkyl; L is -X 1 -X 2 -X 3 -X 4 -X 5 -and;X 1 is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5a 7-12 membered spiro bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, wherein the heterocycloalkyl is optionally substituted with —CH3, or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with —CH3; X 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, 4- to 6-membered cycloalkyl, or 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4 Alkyl-, 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p - or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH3; X 4 is a bond, -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-, -(O-CH2-CH2-CH2) m - or a 5- to 6-membered saturated, partially unsaturated, or fully unsaturated heterocycle having 1 to 3 heteroatoms independently selected from N, O, or S; X 5 is a bond, -C 1~4 alkyl-, -N(R)-, or -C(O)-N(R)-; each R is independently -H or -C 1~3 alkyl; m, n, and p are each independently an integer from 1 to 3; Y is [ka] where each R 2 are independently halo or C1~4 alkyl; each Z is -C(R A )2- or -C(O)-; each R A are independently -H or C 1~4 and q is 0, 1, or 2.

[0100] In some embodiments, the compound of formula (I) has the formula (IB): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1~3 alkyl; L is -X 1 -X 2 -X 3 -X 4 -X 5 -and;X 1 is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 a 7-12 membered spiro bicyclic heterocycloalkyl ring having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, wherein the heterocycloalkyl is optionally substituted with —CH3, or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with —CH3; X 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, 4- to 6-membered cycloalkyl, or 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4Alkyl-, 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p - or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH3; X 4 is a bond, -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-, -(O-CH2-CH2-CH2) m - or a 5- to 6-membered saturated, partially unsaturated, or fully unsaturated heterocycle having 1 to 3 heteroatoms independently selected from N, O, or S; X 5 is a bond, -C 1~4 alkyl-, -N(R)-, or -C(O)-N(R)-; each R is independently -H or -C 1~3 alkyl; m, n, and p are each independently an integer from 1 to 3; Y is [ka] where each R 2 are independently halo or C 1~4 alkyl; each Z is -C(R A )2- or -C(O)-; each R A are independently -H or C 1~4 and q is 0, 1, or 2.

[0101] In some embodiments, the compound of formula (I) is a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 Each of , L, and Z is as defined in the compounds of formula (I).

[0102] In some embodiments, the compound of formula (II) has the formula (II-A) or (II-B): [ka] or a pharmaceutically acceptable salt thereof, wherein X 2 , X 3 , X 4 , X 5 and R 2 are as defined in the compounds of formula (I).

[0103] In some embodiments, the compound of formula (I) has formula (III): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1~3 alkyl; L is -X 1 -X 2 -X 3 -and;X 1 is a 7-12 membered spiro bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with —CH3, or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with —CH3; X 2 is a bond or -C 1~5 Alkyl-; X 3 is a bond, -C 1~4 alkyl- or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH3; Y is [ka] where each R 2 are independently halo or C 1~4 alkyl; each Z is -C(R A )2- or -C(O)-; each R A is independently —H; and q is 0, 1, or 2.

[0104] In some embodiments, the compound of formula (I) has formula (IV): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1~3 alkyl; L is -X 1 -X 2 -X 3 -X 4 -X 5 -and;X 1 is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -( O-CH2-CH2-CH2) m -, -C 1~5 a 7-12 membered spiro bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, wherein the heterocycloalkyl is optionally substituted with —CH3, or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with —CH3; X 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, 4- to 6-membered cycloalkyl, or 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4Alkyl-, 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p - or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH3; X 4 is a bond, -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-, -(O-CH2-CH2-CH2) m - or a 5- to 6-membered saturated, partially unsaturated, or fully unsaturated heterocycle having 1 to 3 heteroatoms independently selected from N, O, or S; X 5 is a bond, -C 1~4 alkyl-, -N(R)-, or -C(O)-N(R)-; each R is independently -H or -C 1~3 alkyl; m, n, and p are each independently an integer from 1 to 3; Y is [ka] where each R 2 are independently halo or C 1~4 alkyl; each Z is -C(R A )2- or -C(O)-; each R A are independently -H or C 1~4 and q is 0, 1, or 2.

[0105] In some embodiments, ring A is: [ka] is selected from.

[0106] In some embodiments, Z is —CH— or —C(O)—.

[0107] In some embodiments, Y is [ka] is.

[0108] In some embodiments, Y is [ka] is.

[0109] In some embodiments, R 1 is methyl, ethyl, or propyl.

[0110] In some embodiments, each R is independently -H or -CH3.

[0111] In some embodiments, X 1 , X 2 , and X 5 At least one of X is -C(O)-N(R)-. For example, X 1 is -C(O)-N(R)-. In another example, X 2 is -(O-CH2-CH2) n -, -(CH2-CH2-O) n - or -C 1~5 and in some instances, X 3 is a bond, -C 1~4 In another example, X is alkyl- or -N(R)-. 4 is a bond or -N(R)-.

[0112] In some embodiments, X 1 -(O-CH2-CH2-CH2) m -, m is 1, and X 2 is -C(O)-N(R)-.

[0113] In some embodiments, X 3is a bond, -C 1~4 alkyl-, 4- to 6-membered cycloalkyl, or -N(R)-.

[0114] In some embodiments, X 1 teeth, [ka] In some of these embodiments, X 2 is -C(O)-, -C 1~5 In some of these embodiments, X is alkyl- or 4- to 6-membered cycloalkyl. 3 is a bond, -C 1~4 Alkyl- or -(CH2-CH2-O) p -It is.

[0115] In some embodiments, X 4 is a bond, [ka] -C 1~4 alkyl-, -CH2-CH2-N(R)-, or -N(R)-.

[0116] In some embodiments, X 5 is a bond, -C 1~4 alkyl-, -N(R)-, or -C(O)-N(R)-.

[0117] In some embodiments, L is [ka] [ka] [ka] [ka] is.

[0118] In some embodiments, the compound of formula (I) has the formula (IA): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1~3 alkyl; L is -X 1 -X 2 -X 3 -X 4 -X 5 -and;X 1 is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 a 7-12 membered spiro bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O, or S (wherein the heterocycloalkyl is optionally substituted with -CH3), or having 1-2 heteroatoms independently selected from N, O, or S; 4-6 membered heterocycloalkyl, where heterocycloalkyl is optionally substituted with —CH3; X 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, 4- to 6-membered cycloalkyl, or 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4 Alkyl-, 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O)p - or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH3; X 4 is a bond, -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-, -(O-CH2-CH2-CH2) m - or a 5- to 6-membered saturated, partially unsaturated, or fully unsaturated heterocycle having 1 to 3 heteroatoms independently selected from N, O, or S; X 5 is a bond, -C 1~4 alkyl-, -N(R)-, or -C(O)-N(R)-; each R is independently -H or -C 1~3 alkyl; m, n, and p are each independently an integer from 1 to 3; Y is [ka] where each R 2 are independently halo or C 1~4 alkyl; each Z is -C(R A )2- or -C(O)-; each R A are independently -H or C 1~4 and q is 0, 1, or 2.

[0119] In some embodiments, the compound of formula (I) has the formula (IB): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1~3 alkyl; L is -X 1 -X 2 -X 3 -X 4 -X 5 -and;X 1 is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m-, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 a 7-12 membered spiro bicyclic heterocycloalkyl ring having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, wherein the heterocycloalkyl is optionally substituted with —CH3, or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with —CH3; X 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O) -, -C 1~5 alkyl-, 4- to 6-membered cycloalkyl, or 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4 Alkyl-, 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p - or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH3; X 4 is a bond, -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-, -(O-CH2-CH2-CH2) m - or a 5- to 6-membered saturated, partially unsaturated, or fully unsaturated heterocycle having 1 to 3 heteroatoms independently selected from N, O, or S; X 5 is a bond, -C 1~4 alkyl-, -N(R)-, or -C(O)-N(R)-; each R is independently -H or -C 1~3 alkyl; m, n, and p are each independently an integer from 1 to 3; Y is [ka] where each R 2 are independently halo or C 1~4 alkyl; each Z is -C(R A )2- or -C(O)-; each R A are independently -H or -C 1~4 and q is 0, 1, or 2.

[0120] In some embodiments, the compound of formula (I) is a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 Each of L, L, and Z is as defined herein for compounds of formula (I), (IA), or (IB).

[0121] In some embodiments, the compound of formula (I) has formula (II-A) or (II-B): [ka] or a pharmaceutically acceptable salt thereof, wherein X 2 , X 3 , X 4 , and X 5 are as defined herein for compounds of formula (I), (IA), or (IB).

[0122] In some embodiments, the compound of formula (I) has formula (III): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 Ha-C 1~3 alkyl; L is -X1 -X 2 -X 3 -and;X 1 is a 7-12 membered spiro bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with —CH3, or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with —CH3; X 2 is a bond or -C 1~5 Alkyl-; X 3 is a bond, -C 1~4 a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from alkyl-, N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH3; Y is [ka] where each R 2 are independently halo or -C 1~4 alkyl; each Z is -C(R A )2- or -C(O)-; each R A is independently —H; and q is 0, 1, or 2.

[0123] In some embodiments, the compound of formula (I) has formula (IV): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1~3 alkyl; L is -X 1 -X 2 -X 3 -X 4 -X 5 -and;X 1 is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2)m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 a 7-12 membered spiro bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, wherein the heterocycloalkyl is optionally substituted with —CH3, or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with —CH3; X 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, 4- to 6-membered cycloalkyl, or 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4 Alkyl-, 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p - or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH3; X 4 is a bond, -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-, -(O-CH2-CH2-CH2) m - or a 5- to 6-membered saturated, partially unsaturated, or fully unsaturated heterocycle having 1 to 3 heteroatoms independently selected from N, O, or S; X 5 is a bond, -C 1~4 alkyl-, -N(R)-, or -C(O)-N(R)-; each R is independently -H or -C 1~3 alkyl; m, n, and p are each independently an integer from 1 to 3; Y is [ka] where each R 2 are independently halo or C 1~4 alkyl; each Z is -C(R A )2- or -C(O)-; each R A are independently -H or -C 1~4 and q is 0, 1, or 2.

[0124] The present invention also provides a method for treating a disease or disorder mediated by BTK, comprising administering to a patient or a biological sample a compound of Formula (A) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, wherein each of the variables included therein is defined herein.

[0125] The present invention also provides a method for synthesizing a compound of formula (A) or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION

[0126] Detailed Description

[0126] The present invention provides bifunctional compounds that induce proteolysis of BTK via the ubiquitin proteolytic pathway. The present invention also provides a compound of formula (A) or a pharmaceutically acceptable salt thereof:

[0127]

[0127] As used herein, the following definitions shall apply unless otherwise stated.

[0128] I. Definition

[0129] For purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0129]

[0130] As used herein, a "protecting group" refers to a moiety or functionality that is introduced into a molecule by chemical modification of a functional group to obtain chemoselectivity in a subsequent chemical reaction. Standard protecting groups are provided in Wuts and Greene: "Greene's Protective Groups in Organic Synthesis," 4th Ed., Wuts, PGM and Greene, TW, Wiley-Interscience, New York: 2006. It is provided.

[0130]

[0131] As described herein, the compounds of the invention may be optionally substituted with one or more substituents as generally described above or as exemplified by particular classes, subclasses, and species of the invention.

[0131]

[0132] As used herein, the term "hydroxyl" or "hydroxy" refers to an --OH moiety.

[0132]

[0133] As used herein, the term "aliphatic" encompasses the terms alkyl, alkenyl, and alkynyl, each of which is optionally substituted as described below.

[0133]

[0134] As used herein, an "alkyl" group refers to a saturated aliphatic hydrocarbon group containing 1 to 12 (e.g., 1 to 8, 1 to 6, or 1 to 4) carbon atoms. The alkyl group can be linear or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-ethylhexyl. Alkyl groups include halo, phospho, alicyclic [e.g., cycloalkyl or cycloalkenyl], heteroalicyclic [e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl, (alicyclic)carbonyl, or (heteroalicyclic)carbonyl], nitro, cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, alkylaminocarbonyl, cycloalkyl ... and optionally substituted with one or more substituents such as cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g., aliphatic amino, cycloaliphatic amino, or heterocycloaliphatic amino], sulfonyl [e.g., aliphatic -SO2-], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy.Without limitation, some examples of substituted alkyl include carboxyalkyl (e.g., HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (e.g., (alkyl-SO2-amino)alkyl), aminoalkyl, amidoalkyl, (alicyclic)alkyl, or haloalkyl.

[0134]

[0135] As used herein, an "alkenyl" group refers to an aliphatic carbon group containing 2 to 8 (e.g., 2 to 12, 2 to 6, or 2 to 4) carbon atoms and at least one double bond. Like an alkyl group, an alkenyl group can be linear or branched. Examples of alkenyl groups include, but are not limited to, allyl, 1- or 2-isopropenyl, 2-butenyl, and 2-hexenyl. Alkenyl groups include halo, phospho, alicyclic [e.g., cycloalkyl or cycloalkenyl], heteroalicyclic [e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl, (alicyclic)carbonyl, or (heteroalicyclic)carbonyl], nitro, cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino], and the like. , heteroarylcarbonylamino, heteroaralkylcarbonylaminoalkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl], amino [e.g., aliphatic amino, alicyclic amino, heteroalicyclic amino, or aliphatic sulfonylamino], sulfonyl [e.g., alkyl-SO2-, alicyclic-SO2-, or aryl-SO2-], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, carboxy, carbamoyl, alicyclic oxy

[0023] The alkenyl may be optionally substituted with one or more substituents such as heteroalicyclicoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy. Without limitation, some examples of substituted alkenyls include cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl, aralkenyl, (alkoxyaryl)alkenyl, (sulfonylamino)alkenyl (e.g., (alkyl-SO-amino)alkenyl), aminoalkenyl, amidoalkenyl, (alicyclic)alkenyl, or haloalkenyl.

[0135]

[0136] As used herein, an "alkynyl" group refers to an aliphatic carbon group containing 2 to 8 (e.g., 2 to 12, 2 to 6, or 2 to 4) carbon atoms and having at least one triple bond. Alkynyl groups can be linear or branched. Examples of alkynyl groups include, but are not limited to, propargyl and butynyl. Alkynyl groups include aroyl, heteroaroyl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, nitro, carboxy, cyano, halo, hydroxy, sulfo, mercapto, sulfanyl [e.g., aliphatic sulfanyl or alicyclic sulfanyl], sulfinyl [e.g., aliphatic sulfinyl or alicyclic sulfinyl], sulfonyl [e.g., aliphatic -SO2-, aliphatic amino-SO2-, or alicyclic -SO2-], amido [e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, cycloalkylcarbonylamino, arylaminocarbonyl, aryl carbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (cycloalkylalkyl)carbonylamino, heteroaralkylcarbonylamino, heteroarylcarbonylamino or heteroarylaminocarbonyl], urea, thiourea, sulfamoyl, sulfamido, alkoxycarbonyl, alkylcarbonyloxy, alicyclic, heteroalicyclic, aryl, heteroaryl, acyl [e.g., (alicyclic)carbonyl or (heteroalicyclic)carbonyl], amino [e.g., aliphatic amino], sulfoxy, oxo, carboxy, carbamoyl, (alicyclic)oxy, (heteroalicyclic)oxy, or (heteroaryl)alkoxy.

[0136]

[0137] As used herein, "amide" encompasses both "aminocarbonyl" and "carbonylamino." These terms, when used alone or in connection with another group, include -N(R X )-C(O)-R Yor -C(O)-N(R X )2, when used internally C(O)-N(R X )- or -N(R X )-C(O)-, where R X and R Y can be aliphatic, alicyclic, aryl, araliphatic, heteroalicyclic, heteroaryl, or heteroaraliphatic. Examples of amido groups include alkylamido (e.g., alkylcarbonylamino or alkylaminocarbonyl), (heteroalicyclic)amido, (heteroaralkyl)amido, (heteroaryl)amido, (heterocycloalkyl)alkylamido, arylamido, aralkylamido, (cycloalkyl)alkylamido, or cycloalkylamido.

[0137]

[0138] As used herein, an "amino" group is -NR X R Y where R X and R Y are independently hydrogen, aliphatic, alicyclic, (alicyclic)aliphatic, aryl, araliphatic, heteroalicyclic, (heteroalicyclic)aliphatic, heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl, (aliphatic)carbonyl, (alicyclic)carbonyl, ((alicyclic)aliphatic)carbonyl, arylcarbonyl, (araliphatic)carbonyl, (heteroalicyclic)carbonyl, ((heteroalicyclic)aliphatic)carbonyl, (heteroaryl)carbonyl, or (heteroaraliphatic)carbonyl, each of which is defined herein and optionally substituted. Exemplary amino groups include: The term "amino" includes -NR when it is not a terminal group (e.g., alkylcarbonylamino). X - where R X has the same meaning as defined above.

[0138]

[0139] As used herein, an "aryl" group, used alone or as part of a larger moiety such as "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to monocyclic (e.g., phenyl); bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl); and tricyclic (e.g., fluorenyl, tetrahydrofluorenyl, or tetrahydroanthracenyl, anthracenyl) ring systems, where the monocyclic ring system is aromatic or at least one of the rings of the bicyclic or tricyclic ring system is aromatic. Bicyclic and tricyclic groups include benzo-fused 2- to 3-membered carbocyclic rings. For example, a benzo-fused group can be a ring system having two or more C 4~8 Aryl includes phenyl fused to a carbocyclic moiety. Aryl includes aliphatic [e.g., alkyl, alkenyl, or alkynyl]; alicyclic; (alicyclic)aliphatic; heteroalicyclic; (heteroalicyclic)aliphatic; aryl; heteroaryl; alkoxy; (alicyclic)oxy; (heteroalicyclic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (in the non-aromatic carbocyclic ring of a benzo-fused bicyclic or tricyclic aryl); nitro; carboxy; amido; acyl [e.g., (aliphatic)carbonyl; (alicyclic)carbonyl; The aryl may be optionally substituted by one or more substituents including ((alicyclic)aliphatic)carbonyl; (araliphatic)carbonyl; (heteroalicyclic)carbonyl; ((heteroalicyclic)aliphatic)carbonyl; or (heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphatic -SO2- or amino-SO2-]; sulfinyl [e.g., aliphatic -S(O)- or alicyclic -S(O)-]; sulfanyl [e.g., aliphatic -S-]; cyano; halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamido; or carbamoyl. Alternatively, the aryl may be unsubstituted.

[0139]

[0140] Non-limiting examples of substituted aryls include haloaryls [e.g., mono-, di(e.g., p,m-dihaloaryls), and (trihalo)aryls]; (carboxy)aryls [e.g., (alkoxycarbonyl)aryls, ((aralkyl)carbonyloxy)aryls, and (alkoxycarbonyl)aryls]; (amido)aryls [e.g., (aminocarbonyl)aryls, (((alkylamino)alkyl)aminocarbonyl)aryls, (alkylcarbonyl)aminoaryls, (arylaminocarbonyl)aryls, and (((heteroaryl)amino)carbonyl)aryls]; aminoaryls [e.g., ((alkylsulfonyl)amino)aryls or ((dialkyl)amino)aryls]; (cyanoalkyl)aryls; (alkoxy)aryls; (sulfamoyl)aryls [e.g., (amino (aminosulfonyl)aryl]; (alkylsulfonyl)aryl; (cyano)aryl; (hydroxyalkyl)aryl; ((alkoxy)alkyl)aryl; (hydroxy)aryl, ((carboxy)alkyl)aryl; (((dialkyl)amino)alkyl)aryl; (nitroalkyl)aryl; (((alkylsulfonyl)amino)alkyl)aryl; ((heteroalicyclic)carbonyl)aryl; ((alkylsulfonyl)alkyl)aryl; (cyanoalkyl)aryl; (hydroxyalkyl)aryl; (alkylcarbonyl)aryl; alkylaryl; (trihaloalkyl)aryl; p-amino-m-alkoxycarbonylaryl; p-amino-m-cyanoaryl; p-halo-m-aminoaryl; or (m-(heteroalicyclic)-o-(alkyl))aryl.

[0140]

[0141] As used herein, "araliphatic," such as an "aralkyl" group, refers to an aliphatic group substituted with an aryl group (e.g., C 1~4 alkyl group) "Aliphatic," "alkyl," and "aryl" are defined herein. An example of an araliphatic such as alkyl group is benzyl.

[0141]

[0142] As used herein, an "aralkyl" group refers to an alkyl group substituted with an aryl group (e.g., C 1~4 "Aralkyl" refers to an aralkyl group (an alkyl group). Both "alkyl" and "aryl" are defined above. An example of an aralkyl group is benzyl. Aralkyl is an aralkyl group that can be selected from the group consisting of aliphatic (e.g., alkyl, alkenyl, or alkynyl, including carboxyalkyl, hydroxyalkyl, or haloalkyl such as trifluoromethyl), alicyclic (e.g., cycloalkyl or cycloalkenyl), (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aryl ... amido [e.g., aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, or heteroaralkylcarbonylamino], cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, or carbamoyl.

[0142]

[0143] As used herein, a "bicyclic ring system" includes a 6- to 12-membered (e.g., 8- to 12- or 9-, 10-, or 11-membered) structure forming two rings, where the two rings have at least one common atom (e.g., two common atoms). Bicyclic ring systems include bicycloaliphatic (e.g., bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatic, bicyclic aryl, and bicyclic heteroaryl.

[0143]

[0144] As used herein, an "alicyclic" group encompasses a "cycloalkyl" group and a "cycloalkenyl" group, each of which is optionally substituted as described below.

[0144]

[0145] As used herein, a "cycloalkyl" group refers to a saturated carbocyclic monocyclic or bicyclic (fused or bridged) ring of 3 to 10 (e.g., 5 to 10) carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl, octahydro, and the like. bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl, adamantyl, or ((aminocarbonyl)cycloalkyl)cycloalkyl.

[0145]

[0146] As used herein, a "cycloalkenyl" group refers to a non-aromatic carbocyclic ring of 3 to 10 (e.g., 4 to 8) carbon atoms having one or more double bonds. Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexa-dienyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, bicyclo[2.2.2]octenyl, or bicyclo[3.3.1]nonenyl.

[0146]

[0147] A cycloalkyl or cycloalkenyl group can be phospho, aliphatic [e.g., alkyl, alkenyl, or alkynyl], alicyclic, (alicyclic)aliphatic, heteroalicyclic, (heteroalicyclic)aliphatic, aryl, heteroaryl, alkoxy, (alicyclic)oxy, (heteroalicyclic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, ( (heteroaliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino, (alicyclic)carbonylamino, ((alicyclic)aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino, (heteroalicyclic)carbonylamino, ((heteroalicyclic)aliphatic)carbonylamino, (heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro, carboxy [e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g., (alicyclic) It can be optionally substituted by one or more substituents such as carbonyl, ((alicyclic)aliphatic)carbonyl, (araliphatic)carbonyl, (heteroalicyclic)carbonyl, ((heteroalicyclic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl], cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkyl-SO2- and aryl-SO2-], sulfinyl [e.g., alkyl-S(O)-], sulfanyl [e.g., alkyl-S-], sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, or carbamoyl.

[0147]

[0148] As used herein, the term "heteroalicyclic" encompasses heterocycloalkyl and heterocycloalkenyl groups, each of which is optionally substituted as described below.

[0148]

[0149] As used herein, a "heterocycloalkyl" group refers to a 3- to 10-membered monocyclic or bicyclic (fused, bridged, or spiro) (e.g., 5- to 10-membered monocyclic or bicyclic) saturated ring structure in which one or more of the ring atoms is a heteroatom (e.g., N, O, S, or a combination thereof). Non-limiting examples of heterocycloalkyl groups include piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl, 1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholinyl, octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydropyridinyl, decahydroquinolinyl, octa ... benzo[b]thiophenyl, 2-oxa-bicyclo[2.2.2]octyl, 1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, decahydro-2,7-naphthyridine, 2,8-diazaspiro[4.5]decane, 2,7-diazaspiro[3.5]nonane, octahydropyrrolo[3,4-c]pyrrole, octahydro-1H-pyrrolo[3,4-b]pyridine, and 2,6-dioxa-tricyclo[3.3.1.0]octyl. 3,7 Monocyclic heterocycloalkyl groups can be fused with a phenyl moiety to form structures such as tetrahydroisoquinoline, which can be classified as heteroaryls.

[0149]

[0150] As used herein, a "heterocycloalkenyl" group refers to a monocyclic or bicyclic (e.g., 5- to 10-membered monocyclic or bicyclic) non-aromatic ring structure having one or more double bonds and in which one or more of the ring atoms is a heteroatom (e.g., N, O, or S). Monocyclic and bicyclic heteroalicyclics are numbered according to standard chemical nomenclature.

[0150]

[0151] Heterocycloalkyl or heterocycloalkenyl groups can be phospho, aliphatic [e.g., alkyl, alkenyl, or alkynyl], alicyclic, (alicyclic)aliphatic, heteroalicyclic, (heteroalicyclic)aliphatic, aryl, heteroaryl, alkoxy, (alicyclic)oxy, (heteroalicyclic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino, (alicyclic)carbonylamino, ((alicyclic)aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino, (heteroalicyclic)carbonylamino, ((heteroalicyclic)aliphatic)carbonylamino, (heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro, carboxy [e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyl]. and optionally substituted by one or more substituents such as aryloxy, acyl [e.g., (alicyclic)carbonyl, ((alicyclic)aliphatic)carbonyl, (araliphatic)carbonyl, (heteroalicyclic)carbonyl, ((heteroalicyclic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl], nitro, cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkylsulfonyl or arylsulfonyl], sulfinyl [e.g., alkylsulfinyl], sulfanyl [e.g., alkylsulfanyl], sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, or carbamoyl.

[0151]

[0152] As used herein, a "heteroaryl" group refers to a monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring atoms, one or more of which is a heteroatom (e.g., N, O, S, or a combination thereof), where the monocyclic ring system is aromatic or at least one of the rings of the bicyclic or tricyclic ring system is aromatic. Heteroaryl groups include benzo-fused ring systems having 2 to 3 rings. For example, benzo-fused groups include benzo (e.g., indolyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophen-yl, quinolinyl, or isoquinolinyl) fused with one or two 4- to 8-membered heteroalicyclic moieties. Some examples of heteroaryl are azetidinyl, pyridyl, 1H-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[1,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolidyl, benzo-1,2,5-thiadiazolyl, or 1,8-naphthyridyl. Other examples of heteroaryls include 1,2,3,4-tetrahydroisoquinoline and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine.

[0152]

[0153] Without limitation, monocyclic heteroaryls include furyl, thiophen-yl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl. Monocyclic heteroaryls are numbered according to standard chemical nomenclature.

[0153]

[0154] Without limitation, bicyclic heteroaryls include indolyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, indolyl, benzo[b]furyl, bexo[b]thiophenyl, indazolyl, benzimidazyl, benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl, or pteridyl. Bicyclic heteroaryls are numbered according to standard chemical nomenclature.

[0154]

[0155] Heteroaryl includes aliphatic [e.g., alkyl, alkenyl, or alkynyl]; alicyclic; (alicyclic)aliphatic; heteroalicyclic; (heteroalicyclic)aliphatic; aryl; heteroaryl; alkoxy; (alicyclic)oxy; (heteroalicyclic)oxy; aryloxy; heteroaryloxy; (araliphatic)oxy; (heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (in a non-aromatic carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroaryl); carboxy; amido; acyl [e.g., aliphatic carbocyclic Heteroaryl is optionally substituted by one or more substituents such as aryl; (alicyclic)carbonyl; ((alicyclic)aliphatic)carbonyl; (araliphatic)carbonyl; (heteroalicyclic)carbonyl; ((heteroalicyclic)aliphatic)carbonyl; or (heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphatic sulfonyl or aminosulfonyl]; sulfinyl [e.g., aliphatic sulfinyl]; sulfanyl [e.g., aliphatic sulfanyl]; nitro; cyano; halo; hydroxy; mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamido; or carbamoyl. Alternatively, heteroaryl may be unsubstituted.

[0155]

[0156] Non-limiting examples of substituted heteroaryls include (halo)heteroaryls [e.g., mono- and di-(halo)heteroaryls]; (carboxy)heteroaryls [e.g., (alkoxycarbonyl)heteroaryls]; cyanoheteroaryls; aminoheteroaryls [e.g., ((alkylsulfonyl)amino)heteroaryls and ((dialkyl)amino)heteroaryls]; (amido)heteroaryls [e.g., aminocarbonylheteroaryls, ((alkylcarbonyl)amino)heteroaryls, ((((alkyl)amino)alkyl)aminocarbonyl)heteroaryls, (((heteroaryl)amino)carbonyl)heteroaryls, ((heteroalicyclic)carbonyl)heteroaryls, and ((alkylcarbonyl)amino)heteroaryls]; (cyanoalkyl)heteroaryls; (alkoxy)heteroaryls; (sulfamoyl)heteroaryls. Heteroaryls include (aminosulfonyl)heteroaryls; (sulfonyl)heteroaryls [e.g., (alkylsulfonyl)heteroaryls]; (hydroxyalkyl)heteroaryls; (alkoxyalkyl)heteroaryls; (hydroxy)heteroaryls; ((carboxy)alkyl)heteroaryls; (((dialkyl)amino)alkyl)heteroaryls; (heteroalicyclic)heteroaryls; (alicyclic)heteroaryls; (nitroalkyl)heteroaryls; (((alkylsulfonyl)amino)alkyl)heteroaryls; ((alkylsulfonyl)alkyl)heteroaryls; (cyanoalkyl)heteroaryls; (acyl)heteroaryls [e.g., (alkylcarbonyl)heteroaryls]; (alkyl)heteroaryls; or (haloalkyl)heteroaryls [e.g., trihaloalkylheteroaryls].

[0156]

[0157] As used herein, "heteroaraliphatic" ( For example, a heteroaralkyl group is an aliphatic group (e.g., C 1~4 "Aliphatic," "alkyl," and "heteroaryl" are defined above.

[0157]

[0158] As used herein, a "heteroaralkyl" group refers to an alkyl group substituted with a heteroaryl group (e.g., C 1~4 "Alkyl" and "heteroaryl" are both defined above. Heteroaralkyl is alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, or carbamoyl. and optionally substituted by one or more substituents such as:

[0158]

[0159] As used herein, "cyclic moiety" and "cyclic group" refer to monocyclic, bicyclic and tricyclic ring systems, including alicyclic, heteroalicyclic, aryl, or heteroaryl, each of which is previously defined.

[0159]

[0160] As used herein, "bridged bicyclic ring system" refers to a bicyclic heteroalicyclic ring system or a bicyclic alicyclic ring system in which the rings are bridged. Examples of cyclic ring systems include adamantanyl, norbornanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, 2-oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.0]octyl. 3,7 Bridged bicyclic ring systems include, but are not limited to, alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkoxy, alkoxycarbonyl ... and arylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, or carbamoyl.

[0160]

[0161] As used herein, an "acyl" group refers to a formyl group or R X -C(O)- (e.g., alkyl-C(O)-, also known as "alkylcarbonyl"), where R X and "alkyl" has been previously defined. Acetyl and pivaloyl are examples of acyl groups.

[0161]

[0162] As used herein, "aroyl" or "heteroaroyl" refers to aryl-C(O)- or heteroaryl-C(O)-. The aryl and heteroaryl portions of the aroyl or heteroaroyl are optionally substituted as previously defined.

[0162]

[0163] As used herein, an "alkoxy" group refers to an alkyl-O- group, where "alkyl" is previously defined.

[0163]

[0164] As used herein, a "carbamoyl" group refers to a group having the structure -O-CO-NR X R Y or -NR X -CO-OR Z where R X and R Y is defined above, and R Z can be aliphatic, aryl, araliphatic, heteroalicyclic, heteroaryl, or heteroaraliphatic.

[0164]

[0165] As used herein, a "carboxy" group includes, when used as a terminal group, -COOH, -COOR X , -OC(O)H, -OC(O)R X or when used as an internal group, refers to -OC(O)- or -C(O)O.

[0165]

[0166] As used herein, a "haloaliphatic" group is an aliphatic group substituted with one to three halogens. For example, the term haloalkyl includes the group -CF3.

[0166]

[0167] As used herein, a "mercapto" group refers to -SH.

[0167]

[0168] As used herein, a "sulfo" group refers to -SO3H or -SO3R when used terminally. Xor, when used internally, -S(O)3-.

[0168]

[0169] As used herein, a "sulfamido" group has the structure -NR when used terminally. X -S(O)2-NR Y R Z When used internally it refers to -NR X -S(O)2-NR Y - refers to where R X , R Y , and R Z is defined above.

[0169]

[0170] As used herein, a "sulfamoyl" group refers to a group having the structure -OS(O)-NR Y R Z where R Y and R Z is defined above.

[0170]

[0171] As used herein, a "sulfonamide" group, when used terminally, has the structure -S(O)2-NR X R Y or -NR X -S(O)2-R Z or when used internally -S(O)2-NR X -or-NR X -S(O)2-, where R X , R Y , and R Z is defined above.

[0171]

[0172] As used herein, a "sulfanyl" group, when used terminally, is -SR X When used internally it refers to -S-, where R X is defined above. Examples of sulfanyl include aliphatic-S-, alicyclic-S-, aryl-S-, and the like.

[0172]

[0173] As used herein, a "sulfinyl" group when used terminally is -S(O)-R X When used internally it refers to -S(O)-, where R X is defined above. Examples of sulfinyl groups include aliphatic -S(O)-, aryl-S(O)-, (alicyclic (aliphatic))-S(O)-, cycloalkyl-S(O)-, heteroalicyclic-S(O)-, heteroaryl-S(O)-, and the like.

[0173]

[0174] As used herein, a "sulfonyl" group, when used terminally, is -S(O)-R X When used internally it refers to -S(O)2-, where R X is defined above. Examples of sulfonyl groups include aliphatic -S(O)-, aryl-S(O)-, (alicyclic(aliphatic))-S(O)-, alicyclic-S(O)-, heteroalicyclic-S(O)-, heteroaryl-S(O)-, (alicyclic(amido(aliphatic)))-S(O)-, and the like.

[0174]

[0175] As used herein, a "sulfoxy" group refers to a group that, when used terminally, is -OS(O)-R X Or -S(O)-OR X When used internally it refers to -OS(O)- or -S(O)-O-, where R X is defined above.

[0175]

[0176] As used herein, a "halogen" or "halo" group refers to fluorine, chlorine, bromine, or iodine.

[0176]

[0177] As used herein, the term "alkoxycarbonyl" encompassed by the term carboxy, used alone or in connection with another group, refers to alkyl-OC(O) - refers to groups such as

[0177]

[0178] As used herein, "alkoxyalkyl" refers to an alkyl group such as alkyl-O-alkyl-, where alkyl is defined above.

[0178]

[0179] As used herein, "carbonyl" refers to --C(O)--.

[0179]

[0180] As used herein, "oxo" refers to =O.

[0180]

[0181] As used herein, the term "phospho" refers to phosphinates and phosphonates. Examples of phosphinates and phosphonates include -P(O)(R P )2, where R P is aliphatic, alkoxy, aryloxy, heteroaryloxy, (alicyclic)oxy, (heteroalicyclic)oxyaryl, heteroaryl, alicyclic or amino.

[0181]

[0182] As used herein, an “aminoalkyl” refers to a group having the structure (R X )2N-alkyl-.

[0182]

[0183] As used herein, a "cyanoalkyl" refers to the structure (NC)-alkyl-.

[0183]

[0184] As used herein, a "urea" group has the structure -NR X -CO-NR Y R Z and when used terminally, the "thiourea" group has the structure -NR X -CS-NR Y R Z When used internally it refers to -NR X -CO-NR Y -or-NR X -CS-NR Y - refers to where R X , R Y , and R Z is defined above.

[0184]

[0185] As used herein, a "guanidine" group refers to a group having the structure -N=C(N(R X R Y ))N(R X R Y ) or -NR X -C(=NR X )NR X R Y where R X and R Y is defined above.

[0185]

[0186] As used herein, the term "amidino" group refers to a group having the structure -C=(NR X )N(R X R Y ), where R X and R Y is defined above.

[0186]

[0187] As used herein, the term "vicinal" generally refers to the arrangement of substituents on a group containing two or more carbon atoms, where the substituents are attached to adjacent carbon atoms.

[0187]

[0188] As used herein, the term "geminal" generally refers to the arrangement of substituents on a group comprising two or more carbon atoms, where the substituents are attached to the same carbon atom.

[0188]

[0189] The terms "terminally" and "internally" refer to the location of a group within a substituent. A group is terminal if it is at the end of a substituent that is not further attached to the rest of the chemical structure. Carboxyalkyl, i.e., R XO(O)C-alkyl is an example of a carboxy group used terminally. When the group is present in the middle of a substituent in a chemical structure, the group is internal. Alkylcarboxy (e.g., alkyl-C(O)O- or alkyl-OC(O)-) and alkylcarboxyaryl (e.g., alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy groups used internally.

[0189]

[0190] As used herein, an "aliphatic chain" refers to a branched or straight chain aliphatic group (e.g., A straight aliphatic chain is a group having the structure -[CH2] v -, where v is 1 to 12. A branched aliphatic chain is a linear aliphatic chain substituted with one or more aliphatic groups. A branched aliphatic chain has the structure -[CQQ] v however, Q must be an aliphatic group in at least one instance. The term aliphatic chain includes alkyl chains, alkenyl chains, and alkynyl chains, where alkyl, alkenyl, and alkynyl are defined above.

[0190]

[0191] The phrase "optionally substituted" is used interchangeably herein with the phrase "substituted or unsubstituted." As described herein, the compounds of the present invention can be optionally substituted with one or more substituents as generally described above or as exemplified by the particular classes, subclasses, and species of the present invention. As described herein, the variables R, R contained in formulas (A), (B), (C), (D), (E), (F), (G), (H), (J), (K), (M), (X), (I), (IA), (IB), (II), (II-A), (II-B), (III), and (IV) described herein are not intended to be limiting. 1 , R 2 The variables R, L, Y, and Z, as well as other variables, encompass specific groups such as alkyl and aryl. Unless otherwise stated, the variables R, R 10 , RA , R 1 , R 2 , L, L 1 Each of the specific groups of D, W, E, V, G, Y, and Z, as well as the other variables, can be optionally substituted with one or more substituents described herein. Each substituent of the specific group can be further optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, alicyclic, heteroalicyclic, heteroaryl, haloalkyl, and alkyl. For example, an alkyl group can be substituted with alkylsulfanyl, which can be optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. As an additional example, the cycloalkyl portion of (cycloalkyl)carbonylamino can be optionally substituted with one to three of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl. When two alkoxy groups are bound to the same atom or adjacent atoms, the two alkoxy groups can form a ring together with the atoms to which they are bound.

[0191]

[0192] As used herein, the term "substituted," whether preceded or not by the term "optionally," generally refers to the replacement of a hydrogen atom in a given structure with the radical of a specified substituent. Specific substituents are described above in the definitions and below in the description of compounds and examples thereof. Unless otherwise stated, an optionally substituted group can have a substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituents can be the same or different at all positions. A ring substituent, such as a heterocycloalkyl, can be attached to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings share one atom. Non-limiting examples of spiroheterocycloalkyls include: [ka] Examples include:

[0192]

[0193] As one skilled in the art will recognize, combinations of substituents envisioned by this invention are those that result in the formation of stable or chemically feasible compounds.

[0193]

[0194] As used herein, the phrase "stable or chemically feasible" refers to a compound that does not change substantially when exposed to conditions that allow for its production, detection, and preferably its recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that does not change substantially when kept in the absence of moisture at a temperature of 40°C or less, or other chemically reactive conditions, for at least one week.

[0194]

[0195] As used herein, "effective amount" is defined as the amount required to provide a therapeutic effect to the treated patient, and is usually determined based on the patient's age, surface area, weight, and condition. The correlation between animal and human dosages (based on milligrams per square meter of body surface) is described by Freireich et al., Cancer Chemother. Rep., 50: 219 (1966). Body surface area can be approximately determined from the patient's height and weight. See, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970). As used herein, "patient" refers to a mammal, including a human.

[0195]

[0196] Unless otherwise stated, structures depicted herein are meant to include all isomers of the structure (e.g., enantiomers, diastereoisomers, and geometric (or conformational) isomers); for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise stated, all tautomers of the compounds of the invention are included within the scope of the invention. Furthermore, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having the present structures except for the replacement of a carbon by a C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays or as therapeutic agents.

[0196]

[0197] Chemical structures and nomenclature were obtained from ChemDraw, version 11.0.1, Cambridge, MA. do.

[0197]

[0198] It is noted that the use of descriptors such as "first," "second," or "third" is used to distinguish between separate elements (e.g., solvents, reaction steps, processes, reagents, etc.) and may or may not refer to the relative order or relative chronology of the elements being described.

[0198] II. Bifunctional Compounds of the Present Invention

[0200] The present invention provides bifunctional compounds that induce proteolysis of targeted BTK via the ubiquitin proteosome pathway. Certain compounds of the present invention also degrade ubiquitin ligases (e.g., E3 ligases).

[0199] A. Bifunctional compounds

[0202] The present invention relates to a compound represented by formula (A) [ka] or a pharmaceutically acceptable salt thereof, wherein W is CH or N; D is a bond or -NH-; ring A is phenyl, a 9-10 membered bicyclic aryl, a 5-6 membered partially or fully unsaturated monocyclic heterocycle, or a 9-10 membered bicyclic heteroaryl, wherein the monocyclic heterocycle and bicyclic heteroaryl of ring A each have 1-3 heteroatoms independently selected from N, O, or S, and ring A is optionally and independently selected from halo, -CN, -COOH, NH, and optionally substituted C 1~6 Ring B is substituted by up to three substituents selected from phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, or 8-10 membered (e.g., 8-9 membered or 9-10 membered) spiro bicyclic heterocycle, Ring B is optionally substituted, and the heteroaryl and heterocycloalkyl of Ring B have 1-3 heteroatoms independently selected from N, O, or S; L is -X 1 -X 2 -X 3 -X 4 -X 5 -and;X 1 is a bond, -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 a 7- to 12-membered spiro or fused bicyclic heterocycloalkyl having 1 to 3 heteroatoms independently selected from alkyl-, N, O, or S, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; and X 1 Each of the monocyclic and bicyclic heterocycloalkyl groups is optionally substituted by —CH3; 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n-, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~8 Alkyl-, -C≡C-, 4- to 6-membered cycloalkyl, -N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from -, N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH; 4 is a bond, -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-, -(O-CH2-CH2-CH2) m -, a 5- to 6-membered saturated, partially unsaturated, or fully unsaturated carbocyclic ring, or a 5- to 6-membered saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from N, O, or S; X 5 is a bond, -C 1~4 alkyl-, -N(R)-, -O-, -C(O)-, or -C(O)-N(R)-; each R is independently -H or -C 1~3 alkyl (e.g., methyl, ethyl, propyl, or isopropyl); and m, n and p are each independently an integer from 1 to 3 (e.g., 1, 2, or 3); and Y is [ka] where each R 2 are independently halo, -CN, or -C 1~4 alkyl, where each C 1~4alkyl is optionally and independently substituted with up to three of halo, —CN, —COOH, —COONH2, —NH2, or —CF3; each R″ and R′′ is independently H or, together with the atom to which they are attached, forms a 5-6 membered partially or fully unsaturated benzo-fused heterocyclic ring; each Z is —C(R A )2- or -C(O)-; each R A are independently -H or -C 1~4 and q is 0, 1, or 2.

[0200]

[0203] All moieties of the linking group L defined in the compounds of formula (A), except for the moieties of the group R, are divalent moieties unless otherwise specified. For example, any alkyl (e.g., n-propyl, n-butyl, n-hexyl, etc.), aryl (e.g., phenyl), cycloalkyl (e.g., cyclopropyl, cyclohexyl, etc.), aryl, heteroaryl, heterocycloalkyl (e.g., piperidine, piperazine, etc.) present in L is divalent unless otherwise specified.

[0201]

[0204] In some embodiments, Ring B is an optionally substituted 5-6 membered heterocycloalkyl having 1-2 nitrogen atoms. For example, Ring B is piperidin-yl, piperizine-yl, or pyrrolidin-yl, any of which may be substituted. All are optionally substituted.

[0202]

[0205] In some embodiments, Ring B is an optionally substituted 5-6 membered heteroaryl having 1-2 heteroatoms independently selected from N and S. For example, Ring B is pyridin-yl, pyrazin-yl, or pyrimidine, any of which is optionally substituted.

[0203]

[0206] In some embodiments, ring B is [ka] where R 10 is halo, -H, -C 1~5 Alkyl (e.g., -C 1~3 alkyl), -3 to 6-membered cycloalkyl, 5 to 6-membered heterocycloalkyl, -CN, -OH, -CF3, -CH2OH, -CH2CH2OH, -C(O)OH, [ka] is.

[0204]

[0207] In some embodiments, ring B is [ka] where R 10 teeth, [ka] and R 1 is C 1~4 For example, ring B is an alkyl group. [ka] where R 10 teeth, [ka] And in one example, ring B is [ka] In another example, R 10 teeth, [ka] is.

[0205]

[0208] In some embodiments, ring A is [ka] wherein ring A' together with the phenyl ring to which it is fused forms a 9-10 membered bicyclic aryl or a 9-10 membered bicyclic heteroaryl, wherein the bicyclic heteroaryl (i.e., the bicyclic heteroaryl containing ring A') has 1-3 heteroatoms independently selected from N, O, or S. For example, ring A can be [ka] is.

[0206]

[0209] In some embodiments, X 1 , X 2 , and X 5 At least one of is —N(R)—, —C(O)—N(R)—, or —CH2—.

[0207]

[0210] In some embodiments, X 1 is -C(O)-N(R)-.

[0208]

[0211] In some embodiments, X 2 is -(O-CH2-CH2) n -, -(CH2-CH2-O) n - or -C 1~5 It is alkyl-.

[0209]

[0212] In some embodiments, X 3 is a bond, -C≡C-, -C 1~4 It is alkyl- or -N(R)-.

[0210]

[0213] In some embodiments, X 4 is a bond, —CH—, or —N(R)—.

[0211]

[0214] In some embodiments, X5 is a bond.

[0212]

[0215] In some embodiments, X 1 -(O-CH2-CH2-CH2) m -, m is 1, and X 2 is -C(O)-N(R)-.

[0213]

[0216] In some embodiments, X 1 -CH2-, -C(O)-, [ka] is.

[0214]

[0217] In some embodiments, X 2 is a bond, -C(O)-, -C 1~5 Alkyl-, [ka] is.

[0215]

[0218] In some embodiments, X 3 is a bond, -C 1~4 alkyl-, 4- to 6-membered cycloalkyl, or -N(R)-.

[0216]

[0219] In some embodiments, X 3 is a bond, -C 1~4 Alkyl-, -NH-, [ka] Or -C≡C-.

[0217]

[0220] In some embodiments, X 4 is a bond, [ka] -C 1~4 alkyl-, -CH2-CH2-N(R)-, or -N(R)-.

[0218]

[0221] In some embodiments, X 5 is a bond, -C 1~4 alkyl-, -N(R)-, or -C(O)-N(R)-.

[0219]

[0222] In some embodiments, L is [ka] [ka] [ka] [ka] [ka] is.

[0220]

[0223] In some embodiments, Y is [ka] is.

[0221]

[0224] In some embodiments, W is N.

[0222]

[0225] In some embodiments, D is a bond.

[0223]

[0226] The present invention also provides a compound represented by formula (B): [ka] or a pharmaceutically acceptable salt thereof, wherein W is CH or N; D is a bond or -NH-; Ring B1 is a 4-6 membered fully saturated, partially unsaturated, or fully unsaturated monocyclic heterocycle or an 8-10 membered fully saturated spiro bicyclic heterocycle, wherein Ring B1 has 1-3 heteroatoms independently selected from N, O, or S and is optionally substituted by 1-3 groups selected from halo, -CH3, -CF3, -C(O)OH, -CH2OH, or a 5-membered heterocycloalkyl (optionally substituted by oxo and having 1-2 heteroatoms independently selected from N or O); L is -X 1 -X 2 -X 3 -and;X 1 is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 a 7- to 12-membered spiro or fused bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, or a 4- to 6-membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein X 1 Each of the monocyclic and bicyclic heterocycloalkyl groups is optionally substituted by —CH3; 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4 Alkyl-, -C≡C-, 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) pa 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms independently selected from -, N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH; each R is independently -H or -C 1~3 alkyl; m, n, and p are each independently an integer from 1 to 3; and Y is [ka] is.

[0224]

[0227] In some embodiments, ring B1 is [ka] and ring B1 is —CH3, —CH2OH, —CH2CH2OH, —C(O)OH, —CF3, —F, [ka] For example, ring B1 is optionally substituted with 1 to 3 groups selected from: [ka] In another example, ring B1 is [ka] is.

[0225]

[0228] In some embodiments, X 1 teeth, [ka] is.

[0226]

[0229] In some embodiments, X 2 is a bond, -C 1~5alkyl-, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S. For example, X 2 is a bond, -C 1~3 Alkyl-, -C(O)-, [ka] is.

[0227]

[0230] In some embodiments, X 3 is a bond, -C 1~4 Alkyl-, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p - or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH3. For example, X 3 is a bond, [ka] is.

[0228]

[0231] In some embodiments, L is [ka] is.

[0229]

[0232] In some embodiments, W is N and D is a bond.

[0230]

[0233] The present invention also provides a compound represented by formula (C): [ka] or a pharmaceutically acceptable salt thereof, wherein W is CH or N; ring C is phenyl or a saturated, partially unsaturated, or fully unsaturated 5-6 membered monocyclic heterocycle having 1-2 heteroatoms independently selected from N, O, or S, wherein each of the phenyl and heterocycle of ring C is optionally substituted; and L is - X 1 -X 2 -X 3 -and;X 1 is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O-(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 alkyl-, a 7-12 membered spiro bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from N, O, or S, or a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein X 1 each of the bicyclic heterocycloalkyl and monocyclic heterocycloalkyl of is optionally substituted by —CH3; 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4 Alkyl-, -C≡C-, 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p a 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms independently selected from -, N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH; each R is independently -H or -C 1~3alkyl; and m, n, and p are each independently an integer from 1 to 3.

[0231]

[0234] In some embodiments, W is N.

[0232]

[0235] In some embodiments, ring C is [ka] For example, ring C is [ka] In another example, ring C is [ka] is.

[0233]

[0236] In some embodiments, X 1 is a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S. For example, X 1 teeth, [ka] In some cases, X 1 teeth, [ka] is.

[0234]

[0237] In some embodiments, X 2 is a bond, -C 1~5 alkyl-, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S. For example, X 2 is a bond or -C 1~3It is alkyl- (e.g., -CH2-).

[0235]

[0238] In some embodiments, X 3 is a 4-6 membered cycloalkyl, -N(R)-, or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH3. For example, X 3 teeth, [ka] In another example, X 3 teeth, [ka] is.

[0236]

[0239] In some embodiments, L is [ka] For example, L is [ka] is.

[0237]

[0240] The present invention also provides a compound represented by formula (D) [ka] or a pharmaceutically acceptable salt thereof, wherein W is CH or N; and ring A is [ka] and L is -X 1 -X 2 -X 3 -and;X 1 -C1~5 alkyl- or a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, where X 1 is optionally substituted by —CH3; 2 is a bond, -C 1~5 alkyl- or a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, where X 1 is optionally substituted by —CH3; 3 is a bond, -C 1~4 alkyl-, a 4-6 membered monocyclic cycloalkyl, or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH3; Y is [ka] and R 10 is halo, -H, -C 1~5 Alkyl, -3 to 6-membered cycloalkyl, 5 to 6-membered heterocycloalkyl, -CN, -OH, -CF3, -CH2OH, -CH2CH2OH, -C(O)OH, [ka] is.

[0238]

[0241] In some embodiments, ring A is [ka] is.

[0239]

[0242] In some embodiments, X 1is a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, where X 1 The monocyclic heterocycloalkyl of the formula: is optionally substituted by —CH3. For example, X 1 teeth, [ka] is.

[0240]

[0243] In some embodiments, X 2 is a bond, -C 1~5 alkyl-, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S. For example, X 2 is a bond or -C 1~4 It is alkyl-.

[0241]

[0244] In some embodiments, X 3 is a bond, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S. For example, X 3 teeth, [ka] is.

[0242]

[0245] In some embodiments, L is [ka] is.

[0243]

[0246] In some embodiments, R 10 is halo, -H, -C 1~5 Alkyl (e.g., -C 1~3alkyl), -3- to 6-membered cycloalkyl, -5- to 6-membered heterocycloalkyl, -CN, -OH, -CF, -CHOH, -C(O)OH, or -CHCHOH. For example, R 10 is halo, -H, C 1~3 alkyl, CF, —CHOH, —C(O)OH, or —CHCHOH. 10 teeth, [ka] is.

[0244]

[0247] In some embodiments, R 10 teeth, [ka] is.

[0245]

[0248] In some embodiments, R 10 teeth, [ka] is.

[0246]

[0249] In some embodiments, the compound of formula (D) is (D-1) [ka] or a pharmaceutically acceptable salt thereof, wherein W is CH or N; ring A is [ka] and L is -X 1 -X 2 -X 3 -and;X 1 -C 1~5alkyl- or a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, where X 1 is optionally substituted by —CH3; 2 is a bond, -C 1~5 alkyl- or a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, where X 1 is optionally substituted by —CH3; 3 is a bond, -C 1~4 alkyl-, a 4-6 membered monocyclic cycloalkyl, or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH3; Y is [ka] and R 10 teeth, [ka] is.

[0247]

[0250] In some embodiments, ring A is [ka] is.

[0248]

[0251] In some embodiments, X 1 is a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, where X 1 The monocyclic heterocycloalkyl of the formula: is optionally substituted by —CH3. For example, X 1 teeth, [ka] is.

[0249]

[0252] In some embodiments, X 2 is a bond, -C 1~5 alkyl-, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S. For example, X 2 is a bond or -C 1~4 It is alkyl-.

[0250]

[0253] In some embodiments, X 3 is a bond, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S. For example, X 3 teeth, [ka] is.

[0251]

[0254] In some embodiments, L is [ka] is.

[0252]

[0255] In some embodiments, R 10 teeth, [ka] is.

[0253]

[0256] In some embodiments, R 10 teeth, [ka] is.

[0254]

[0257] In some embodiments, the compound of formula (D) or the compound of formula (D-1) has formula (D-2): [ka] or a pharmaceutically acceptable salt thereof, wherein rings A, L, Y, and R 10 The term is as defined in the compounds of formula (A), (D), and (D-1).

[0255]

[0258] In some embodiments, ring A is [ka] is.

[0256]

[0259] In some embodiments, X 1 is a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, where X 1 The monocyclic heterocycloalkyl of the formula: is optionally substituted by —CH3. For example, X 1 teeth, [ka] is.

[0257]

[0260] In some embodiments, X 2 is a bond, -C 1~5 alkyl-, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S. For example, X 2 is a bond or -C 1~4 It is alkyl-.

[0258]

[0261] In some embodiments, X3 is a bond, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S. For example, X 3 teeth, [ka] is.

[0259]

[0262] In some embodiments, L is [ka] is.

[0260]

[0263] In some embodiments, R 10 teeth, [ka] is.

[0261]

[0264] In some embodiments, R 10 teeth, [ka] is.

[0262]

[0265] The present invention also provides a compound represented by formula (E): [ka] or a pharmaceutically acceptable salt thereof, wherein D is a bond or —NH—; W is N or CH; ring A is phenyl, a 9-10 membered bicyclic aryl, a 5-6 membered partially or fully unsaturated monocyclic heterocycle, or a 9-10 membered bicyclic heteroaryl, wherein the monocyclic heterocycle and bicyclic heteroaryl of ring A each have 1-3 heteroatoms independently selected from N, O, or S; ring B is an optionally substituted 5-6 membered saturated, partially unsaturated, or fully unsaturated monocyclic heterocycle, or an optionally substituted 8-10 membered (e.g., 8-9 membered or 9-10 membered) spiro bicyclic heterocycle, wherein ring B has 1-3 heteroatoms independently selected from N, O, or S; L is -X 1 -X 2 -X 3 -X 4 -X 5 -and;X 1 is a bond, -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 alkyl-, a 7-12 membered spiro bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from N, O, or S, or a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein X 1 Each of the monocyclic and bicyclic heterocycloalkyl groups is optionally substituted by —CH3; 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4 Alkyl-, -C≡C-, 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p-, -(CH2-CH2-O) p a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from -, N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH; 4 is a bond, -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-, -(O-CH2-CH2-CH2) m -, a 5- to 6-membered saturated, partially unsaturated, or fully unsaturated carbocyclic ring, or a 5- to 6-membered saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from N, O, or S; X 5 is a bond, —N(R)—, or —C(O)—N(R)—; each R is independently —H or —C 1~3 alkyl; m, n, and p are each independently an integer from 1 to 3; and Y is [ka] where X 1 , X 2 , X 3 , X 4 , and X 5 at least one of which has a nitrogen atom, and Y is X 1 , X 2 , X 3 , X 4 , or X 5 is directly bonded to L at the nitrogen atom of

[0263]

[0266] In some embodiments, ring B is [ka] where R 10 teeth, [ka] and R 1 is C 1~4 For example, ring B is an alkyl group. [ka] where R 10 teeth, [ka] In another example, ring B is [ka] is.

[0264]

[0267] In some embodiments, R 10 teeth, [ka] is.

[0265]

[0268] In some embodiments, ring A is [ka] is.

[0266]

[0269] In some embodiments, X 5 is -N(R)-.

[0267]

[0270] In some embodiments, X 5 is -C(O)-N(R)-.

[0268]

[0271] In some embodiments, X 5 is a bond.

[0269]

[0272] In some embodiments, L is [ka] [ka] [ka] is.

[0270]

[0273] In some embodiments, Y is [ka] is

[0271]

[0274] The present invention also provides a compound represented by formula (F) [ka] or a pharmaceutically acceptable salt thereof, wherein W is CH or N; and L is -X 1 -X 2 -X 3 -and;X 1 is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 alkyl-, a 7-12 membered spiro bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from N, O, or S, or a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein X 1 Each of the monocyclic and bicyclic heterocycloalkyl groups is optionally substituted by —CH3; 2 is a bond, -C 1~5 Alkyl-, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5alkyl-, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4 Alkyl-, -C≡C-, 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p a 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms independently selected from -, N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH; each R is independently -H or -C 1~3 alkyl; m, n, and p are each independently an integer from 1 to 3; and Y is [ka] is.

[0272]

[0275] In some embodiments, W is N.

[0273]

[0276] In some embodiments, Y is [ka] is.

[0274]

[0277] In some embodiments, X 1 is a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, where X 1 Each monocyclic heterocycloalkyl of is optionally substituted by -CH3. For example, X 1 teeth, [ka] In one example, X 1 teeth, [ka] is.

[0275]

[0278] In some embodiments, X 2 is a bond or -C 1~5 It is alkyl-.

[0276]

[0279] In some embodiments, X 3 is a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S. For example, X 3 teeth, [ka] In one example, X 3 teeth, [ka] is.

[0277]

[0280] In some embodiments, L is [ka] is.

[0278]

[0281] In some embodiments, L is [ka] is.

[0279]

[0282] In some embodiments, W is N and L is [ka] is.

[0280]

[0283] The present invention also provides a compound represented by formula (G): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , L, and Y are expressed by the formula ( A) as defined for the compound.

[0281]

[0284] In some embodiments, R 1 is methyl.

[0282]

[0285] In some embodiments, Y is [ka] is.

[0283]

[0286] In some embodiments, W is N.

[0284]

[0287] The present invention also provides a compound represented by formula (H) [ka] or a pharmaceutically acceptable salt thereof, wherein ring B, R 2 , Z, W, D, and q are as defined in the compounds of formula (A).

[0285]

[0288] In some embodiments, q is 0.

[0286]

[0289] The present invention also provides a compound represented by formula (J): [ka] or a pharmaceutically acceptable salt thereof, wherein the rings B, D, W, R 2 , q, and L are as defined in the compounds of formula (A).

[0287]

[0290] The present invention also provides a compound represented by formula (K): [ka] or a pharmaceutically acceptable salt thereof, wherein ring A is [ka] wherein ring A is optionally and independently selected from halo, -CN, -carboxyl, -NH, and optionally substituted -C 1~6 Alkyl (e.g., optionally substituted -C 1~3 and each of E and G is independently 5-6 membered heterocycloalkyl, wherein each heterocycloalkyl contains at least one nitrogen atom. 2 , q, R", R"', and Ring A' are as defined in compounds of Formula (A). In some embodiments, Ring A' together with the phenyl ring to which it is fused forms a 9-10 membered bicyclic aryl or a 9-10 membered bicyclic heteroaryl, wherein the bicyclic heteroaryl has 1-3 heteroatoms independently selected from N, O, or S.

[0288]

[0291] In some embodiments, D is a bond and W is a nitrogen atom.

[0289]

[0292] The present invention also provides a compound represented by formula (M) [ka] or a pharmaceutically acceptable salt thereof, wherein R 10A is -H, [ka] where R 1 is C1~4 is alkyl; X 1 -C 1~5 alkyl-; Ring C-1 is a 5- to 6-membered heterocycloalkyl having one nitrogen atom; and Y is [ka] is.

[0290]

[0293] In some embodiments, R 10A is -H or [ka] is.

[0291]

[0294] In some embodiments, R 10A teeth, [ka] and R 1 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or isobutyl. For example, R 1 is methyl.

[0292]

[0295] In some embodiments, X 1 is methylene, ethylene, or propylene. For example, X 1 is methylene.

[0293]

[0296] In some embodiments, ring C-1 is [ka] For example, ring C-1 is [ka] is.

[0294]

[0297] The present invention also provides a compound represented by formula (X) [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1~3 alkyl; ring A is phenyl, a 5- to 6-membered partially or fully unsaturated monocyclic heterocycle, a 9- to 10-membered bicyclic aryl, or a 9- to 10-membered bicyclic heteroaryl, wherein the heterocycle and bicyclic heteroaryl of ring A each independently have 1 to 3 heteroatoms independently selected from N, O, or S; L is -X 1 -X 2 -X 3 -X 4 -X 5 -and;X 1 is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 7-12 membered spiro bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O, or S (wherein X 1 optionally substituted by —CH3), or a 4-6 membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S (wherein X 1 wherein the monocyclic heterocycloalkyl is optionally substituted by —CH3; 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 The conclusion is -C 1~4Alkyl-, -C≡C-, 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from -, N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH; 4 is a bond, -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-, -(O-CH2-CH2-CH2) m - or a 5-6 membered saturated, partially unsaturated, or fully unsaturated carbocyclic ring having 0-3 heteroatoms independently selected from N, O, or S; X 5 is a bond, -C 1~4 alkyl-, -N(R)-, or -C(O)-N(R)-; each R is independently -H or -C 1~3 alkyl; m, n, and p are each independently an integer from 1 to 3; Y is [ka] where each R 2 are independently halo or C 1~4 alkyl; each Z is -C(R A )2- or -C(O)-; each R A are independently -H or C 1~4 and q is 0, 1, or 2.

[0295]

[0298] In one example, the compound of formula (X) is a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1~3 alkyl; ring A is phenyl, a 9-10 membered bicyclic aryl, or a 9-10 membered bicyclic heteroaryl having 1-3 heteroatoms independently selected from N, O, or S; L is -X1 -X 2 -X 3 -X 4 -X 5 -and;X 1 is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 a 7-12 membered spiro bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, wherein the heterocycloalkyl is optionally substituted with —CH3, or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with —CH3; X 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, 4- to 6-membered cycloalkyl, or 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4 Alkyl-, 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from -, N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH; 4 is a bond, -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-, -(O-CH2-CH2-CH2) m - or a 5- to 6-membered saturated, partially unsaturated, or fully unsaturated heterocycle having 1 to 3 heteroatoms independently selected from N, O, or S; X 5 is a bond, -C 1~4alkyl-, -N(R)-, or -C(O)-N(R)-; each R is independently -H or -C 1~3 alkyl; m, n, and p are each independently an integer from 1 to 3 (e.g., 1, 2, or 3); Y is [ka] where each R 2 are independently halo or -C 1~4 alkyl; each Z is -C(R A )2- or -C(O)-; each R A are independently -H or -C 1~4 and q is 0, 1, or 2.

[0296]

[0299] In some embodiments, q is 0. In other embodiments, q is 1 and R 2 is -F.

[0297]

[0300] In some embodiments, Z is —CH 2 — or —C(O)—.

[0298]

[0301] In some embodiments, Y is [ka] is.

[0299]

[0302] In other embodiments, Y is [ka] is.

[0300]

[0303] In some embodiments, R 1 Ha-C 1~3 alkyl. For example, R 1 is methyl, ethyl, propyl, or iso-propyl. 1 is methyl.

[0301]

[0304] In some embodiments, each R is independently -H or -CH. For example, each R is -H.

[0302]

[0305] In some embodiments, X 1 is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 In some embodiments, X is a 7-12 membered spiro bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH3. 1 is -C(O)-N(R)-. For example, X 1 is —C(O)—N(H)—, —C(O)—N(CH)—, or —C(O)—N(CHCH)—. In other embodiments, X 1 is a 5-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with -CH3. For example, X 1 teeth, [ka] In another example, X 1 is a 7-10 membered spiro bicyclic heterocycloalkyl ring having 1-3 heteroatoms (e.g., N) independently selected from N, O, or S. For example, X 1 teeth, [ka] In another embodiment, X 1 is -(O-CH2-CH2)m -or -(O-CH2-CH2-CH2) m -, where m is 1, 2, or 3. For example, X 1 is -(O-CH2-CH2) m -or -(O-CH2-CH2-CH2) m - and m is 1. In another example, X 1 is -(O-CH2-CH2) m -or -(O-CH2-CH2-CH2) m - and m is 2. In some embodiments, X 1 Ha-C 1~5 alkyl-. For example, X 1 is methylene, ethylene, propylene, butylene, etc. In some embodiments, X 1 -CH2-, -C(O)-, [ka] is.

[0303]

[0306] In some embodiments, X 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, 4- to 6-membered cycloalkyl, or 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S. In some embodiments, X 2 is a bond. In some embodiments, X 2 is -(O-CH2-CH2) n -, -(CH2-CH2-O) n - or -C 1~5 alkyl-, where n is 1, 2, or 3. For example, X 1 is -C(O)-N(R)-, and X 2 is -(O-CH2-CH2) n -, -(CH2-CH2-O) n - or -C1~5 In some instances, X is alkyl-. 2 is -(O-CH2-CH2) n -or-(CH2-CH2-O) n -, where n is 1 or 2. In another example, X 2 Ha-C 1~5 alkyl-. For example, X 2 is methylene, ethylene, propylene, butylene, etc. In other examples, X 2 is a bond, -CH2-, -CH2-CH2-, or -CH2-CH2-CH2-. In some examples, X 2 is a 4- to 6-membered cycloalkyl. For example, X 2 teeth, [ka] In another example, X 2 is a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S. For example, X 2 teeth, [ka] is.

[0304]

[0307] In some embodiments, X 3 is a bond, -C 1~4 Alkyl-, 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p and a 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from -, N, O, or S, wherein the heterocycloalkyl is substituted by -CH3. In some embodiments, X is optionally substituted with 3 is a bond. In some embodiments, X 3 is methyl, ethyl, propyl, iso-propyl, butyl, etc. In some embodiments, X 3is cyclopentyl or cyclohexyl. In some embodiments, X 3 is —N(H)—. And in other embodiments, X 3 is -(O-CH2-CH2) p -or-(CH2-CH2-O) p -, where p is 1 or 2.

[0305]

[0308] In some embodiments, X 4 is a bond, -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-, -(O-CH2-CH2-CH2) m -, or a 5-6 membered saturated, partially unsaturated, or fully unsaturated heterocycle having 1-3 heteroatoms independently selected from N, O, or S. In some embodiments, X 4 is a bond, [ka] -C 1~4 alkyl-, -CH2-CH2-N(R)-, or -N(R)-. For example, X 4 is -CH2-CH2-N(H)-, or -N(H)-. In another example, X 4 is methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, etc.

[0306]

[0309] In some embodiments, X 5 is a bond, -C 1~4 In some embodiments, X is alkyl-, -N(R)-, or -C(O)-N(R)-. 5 is a bond. In some embodiments, X 5 is methyl, ethyl, propyl, iso-propyl, butyl, etc. In some embodiments, X 5 is —N(H)— or —C(O)—N(H)—.

[0307]

[0310] In some embodiments, L is [ka] [ka] [ka] [ka] is selected from.

[0308]

[0311] The present invention also provides a compound of formula (IA): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1~3 alkyl; L is -X 1 -X 2 -X 3 -X 4 -X 5 -and;X 1 is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 a 7-12 membered spiro bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, wherein the heterocycloalkyl is optionally substituted with —CH3, or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with —CH3; X 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n-, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, 4- to 6-membered cycloalkyl, or 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4 Alkyl-, 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p - or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH3; X 4 is a bond, -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-, -(O-CH2-CH2-CH2) m - or a 5- to 6-membered saturated, partially unsaturated, or fully unsaturated heterocycle having 1 to 3 heteroatoms independently selected from N, O, or S; X 5 is a bond, -C 1~4 alkyl-, -N(R)-, or -C(O)-N(R)-; each R is independently -H or -C 1~3 alkyl; m, n, and p are each independently an integer from 1 to 3; Y is [ka] where each R 2 are independently halo or -C 1~4 alkyl; each Z is -C(R A )2- or -C(O)-; each R A are independently -H or -C 1~4 and q is 0, 1, or 2.

[0309]

[0312] In other embodiments, each of the variables in formula (IA) is as defined herein for compounds of formula (X) or (I).

[0310]

[0313] The present invention also provides a compound represented by formula (IB): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1~3 alkyl; L is -X 1 -X 2 -X 3 -X 4 -X 5 -and;X 1 is -C(O)-N(R)-, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 a 7-12 membered spiro bicyclic heterocycloalkyl ring having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, wherein the heterocycloalkyl is optionally substituted with —CH3, or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with —CH3; X 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, 4- to 6-membered cycloalkyl, or 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4 Alkyl-, 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p - or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH3; X 4 is a bond, -CH2-CH2-N(R)-, -N(R)-, -C1~4 Alkyl-, -(O-CH2-CH2-CH2) m - or a 5- to 6-membered saturated, partially unsaturated, or fully unsaturated heterocycle having 1 to 3 heteroatoms independently selected from N, O, or S; X 5 is a bond, -C 1~4 alkyl-, -N(R)-, or -C(O)-N(R)-; each R is independently -H or -C 1~3 alkyl; m, n, and p are each independently an integer from 1 to 3; Y is [ka] where each R 2 are independently halo or C 1~4 alkyl; each Z is -C(R A )2- or -C(O)-; each R A are independently -H or C 1~4 and q is 0, 1, or 2.

[0311]

[0314] In other embodiments, each of the variables in formula (IB) is as defined herein for compounds of formula (X) or (I).

[0312]

[0315] The present invention also provides a compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 Each of L, L, and Z is as defined herein for compounds of formula (X), (I), (IA), or (IB).

[0313]

[0316] In some embodiments, the compound of formula (II) has formula (II-A) or (II-B): [ka] or a pharmaceutically acceptable salt thereof, wherein X 2 , X 3 , X 4 , and X 5 are as defined herein for compounds of formula (X), (I), (IA), (IB), or (II).

[0314]

[0317] The present invention also provides a compound represented by formula (III) [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1~3 alkyl; L is -X 1 -X 2 -X 3 -and;X 1 is a 7-12 membered spiro bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with —CH3, or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with —CH3; X 2 is a bond or -C 1~5 Alkyl-; X 3 is a bond, -C 1~4 a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from alkyl-, N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH3; Y is [ka] where each R 2 are independently halo or -C 1~4 alkyl; each Z is -C(R A )2- or -C(O)-; each R Ais independently —H; and q is 0, 1, or 2.

[0315]

[0318] The present invention also provides a compound represented by formula (IV) [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1~3 alkyl; L is -X 1 -X 2 -X 3 -X 4 -X 5 -and;X 1 is -C(O)-N(R) -, -N(R)-C(O)-, -(O-CH2-CH2) m -, -O(C6H4)-, -(O-CH2-CH2-CH2) m -, -C 1~5 a 7-12 membered spiro bicyclic heterocycloalkyl having 1-3 heteroatoms independently selected from alkyl-, N, O, or S, wherein the heterocycloalkyl is optionally substituted with —CH3, or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with —CH3; X 2 is the bond, -(O-CH2-CH2) n -, -(CH2-CH2-O) n -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C 1~5 alkyl-, 4- to 6-membered cycloalkyl, or 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, or S; X 3 is a bond, -C 1~4 Alkyl-, 4-6 membered cycloalkyl, -N(R)-, -(O-CH2-CH2) p -, -(CH2-CH2-O) p- or a 4-6 membered heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted by -CH3; X 4 is a bond, -CH2-CH2-N(R)-, -N(R)-, -C 1~4 Alkyl-, -(O-CH2-CH2-CH2) m - or a 5- to 6-membered saturated, partially unsaturated, or fully unsaturated heterocycle having 1 to 3 heteroatoms independently selected from N, O, or S; X 5 is a bond, -C 1~4 alkyl-, -N(R)-, or -C(O)-N(R)-; each R is independently -H or -C 1~3 alkyl; m, n, and p are each independently an integer from 1 to 3; Y is [ka] where each R 2 are independently halo or -C 1~4 alkyl; each Z is -C(R A )2- or -C(O)-; each R A are independently -H or -C 1~4 and q is 0, 1, or 2.

[0316] B. General Synthetic Scheme General Procedure 1: Amide Coupling

[0321] A mixture of amine (0.03 mmol), acid (0.03 mmol), HATU (0.04 mmol), DIPEA (0.15 mmol), and DMF was stirred at room temperature for 30 minutes. The mixture was purified by HPLC (HO / MeCN containing 0.1% TFA) to give the amide product. An exemplary amide coupling is provided in Scheme 1 below, which shows the coupling of 3-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propoxy)propanoic acid and (R)-3-((4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide. The resulting amide was reacted as described above to provide 3-((4-(9-(3-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propoxy)propanoyl)-3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)-5-((R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide (compound 57).

[0317] Scheme 1: Synthesis of compound 57 via amide formation [ka]

[0323] Other amide-containing compounds of the present invention synthesized using General Procedure 1 are compounds 2-9, 10-14, 19, 20, 22-28, 61, 62, 63, and 67.

[0318] General Procedure 2: Reductive Amination

[0325] A mixture of the amine TFA salt (0.07 mmol), aldehyde (0.1 mmol), triethylamine (0.28 mmol), and DCE was stirred at room temperature for 10 min. NaBH(OAc) (0.14 mmol) was added, and the mixture was stirred at room temperature for 2 h. The mixture was filtered through Celite, washed with CHCl, concentrated, and purified by HPLC (H0 / MeCN with 0.1% TFA) to give the amine product. An exemplary reductive amination is provided in Scheme 2, in which (R)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-3-((4-(piperidin-4-yl)phenyl)amino)pyrazine-2-carboxamide is converted to (3R)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-3-carboxamide as described above. Reaction with methyl ketone gave 3-((4-(1-(((3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-3-yl)methyl)piperidin-4-yl)phenyl)amino)-5-((R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide (compound 32).

[0319] Scheme 2: Synthesis of compound 32 by reductive amination [ka]

[0327] Other amine-containing compounds of the present invention synthesized using General Procedure 2 are compounds 33, 46, 56, 15-18, 21, 31, 48-52, 54, 59, 60, 35, 36, and 38-45.

[0320] Scheme 3: Synthesis of compounds of the present invention [ka]

[0329] Intermediate 3-1, which can be generated by deesterifying intermediate 1-6, is treated with an amine Y-NH under coupling conditions to generate compounds of the invention 3-2, where the terminal linking group of L is an amide.

[0321] General Procedure 3: Fluoroaryl Substitution

[0331] A mixture of amine (0.22 mmol), aryl fluoride (0.22 mmol), DIPEA (0.88 mmol), and DMF (1 mL) was stirred for 16 h at 90° C. The mixture was purified by HPLC (HO / MeCN containing 0.1% TFA) to give the desired product. An exemplary aryl fluoride substitution is provided in Scheme 3, where (R)-3-((4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide is reacted with 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione as described above to give 3-((4-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-1,3-dione). (R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide (compound 34) is provided.

[0322] Scheme 3: Synthesis of compound 34 via aryl fluoride substitution [ka] Other arylamine-containing compounds of the present invention synthesized using General Procedure 3 are compounds 55, 29, 47, 53, 58, 64-66, 37, and 30.

[0323]

[0333] Using the synthetic scheme above, the compounds in Table 1 were synthesized.

[0324]

Table 1

[0325]

Table 2

[0326]

Table 3

[0327]

Table 4

[0328]

Table 5

[0329]

Table 6

[0330]

Table 7

[0331]

Table 8

[0332]

Table 9

[0333]

Table 10

[0334]

Table 11

[0335]

Table 12

[0336]

Table 13

[0337]

Table 14

[0338]

Table 15

[0339] Table 16

[0340]

Table 17

[0341]

Table 18

[0342] Table 19

[0343] Table 20

[0344] Table 21

[0345] Table 22

[0346] Table 23

[0347] Table 24

[0348] Table 25

[0349] Table 26

[0350] Table 27

[0351] Table 28

[0352] Table 29

[0353] Table 30

[0354] Table 31

[0355] Table 32

[0356] [Table 33]

[0357] [Table 34]

[0358] [Table 35]

[0359] [Table 36]

[0360] [Table 37]

[0361] [Table 38]

[0362] [Table 39]

[0363] III. Use, Formulation, and Administration A. Pharmaceutical Compositions

[0337] The compounds described herein can be formulated into pharmaceutical compositions further comprising a pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle. In one embodiment, the present invention provides a pharmaceutical composition comprising the compound of the present invention described above and a pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle. In one embodiment, the present invention is a pharmaceutical composition comprising an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle. Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients, or carriers appropriately selected with respect to the intended form of administration and consistent with conventional pharmaceutical practice.

[0364]

[0338] According to another embodiment, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof. and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of Formula (A), (B), (C), (D), (E), (F), (G), (H), (J), (K), (M), (I), (II), (III), and / or (X), where a "therapeutically effective amount" is an amount that is effective (a) to measurably degrade BTK (or reduce the amount of BTK) in a biological sample or in a patient, or (b) to treat and / or ameliorate a disease or disorder mediated by BTK.

[0365]

[0339] The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0366] It will also be appreciated that some of the compounds of the present invention can exist in free form for treatment, or, where appropriate, as pharmaceutically acceptable derivatives thereof (e.g., salts). According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other addition product or derivative that, when administered to a patient in need thereof, can provide, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.

[0367]

[0341] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like.

[0368] Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. The compounds of the present invention Pharmaceutically acceptable salts include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts include salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, Salts derived from appropriate bases include hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1~4 (alkyl) quaternization salts. The present invention also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include, where appropriate, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Counterions which may be formed include non-toxic ammonium, quaternary ammonium, and amine cations.

[0369] Pharmaceutically acceptable carriers may contain inactive ingredients that do not significantly inhibit the biological activity of compounds. Pharmaceutically acceptable carriers must be biocompatible, for example, non-toxic, non-inflammatory, non-immunogenic, or must not cause other undesirable reactions or side effects when administered to a subject. Standard pharmaceutical formulation techniques can be used.

[0370] As used herein, pharmaceutically acceptable carriers, adjuvants, or vehicles include any and all solvents, diluents, or other liquid vehicles, dispersing or suspending aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, that are appropriate for the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for their preparation. To the extent that any conventional carrier medium is incompatible with the compounds described herein, for example, by producing any undesired biological effects or otherwise interacting in a deleterious manner with any other components of the pharmaceutically acceptable compositions, the use of such conventional carrier medium is considered to be within the scope of the present invention. As used herein, the phrase "side effects" encompasses undesired and adverse effects of a therapy (e.g., a prophylactic or therapeutic agent). Side effects are always unwanted, but unwanted effects are not necessarily adverse. Adverse effects of a treatment (e.g., a prophylactic or therapeutic agent) can be harmful, uncomfortable, or dangerous. Side effects include, but are not limited to, fever, chills, lethargy, gastrointestinal toxicity (including gastric and intestinal ulcers and erosions), nausea, vomiting, neurotoxicity, nephrotoxicity, kidney toxicity (including conditions such as papillary necrosis and chronic interstitial nephritis), hepatotoxicity (including elevated serum liver enzyme levels), bone marrow toxicity (including leukopenia, bone marrow suppression, thrombocytopenia, and anemia), dry mouth, metallic taste, prolonged pregnancy, weakness, somnolence, pain (including myalgia, bone pain, and headache), hair loss, asthenia, dizziness, extrapyramidal symptoms, akathisia, cardiovascular disorders, and sexual dysfunction.

[0371] Some examples of materials that can function as pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., twin 80, phosphate, glycine , sorbic acid, or potassium sorbate), a mixture of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, methylcellulose, hydroxypropylmethylcellulose, wool fat, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate. acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, releasing agents, coatings, sweeteners, flavorings, and fragrances. Preservatives and antioxidants may also be present in the composition according to the judgment of the formulator.

[0372] As used herein, the term "measurably degrade" refers to a measurable decrease in (a) BTK activity between a sample containing a compound of the invention and BTK and an equivalent sample containing BTK without the compound, or b) the concentration of BTK in a sample over time.

[0373] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intraocular, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present invention may be aqueous or oily suspensions. These suspensions may be formulated using suitable dispersing or wetting agents and suspending agents according to techniques known in the art. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0374] For this purpose, any bland fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans, and pharmaceuticals, may also be used. Other emulsifiers or bioavailability enhancers commonly used in the manufacture of physiologically acceptable solid, liquid, or other dosage forms may also be used for the formulation.

[0375]

[0349] The pharmaceutically acceptable compositions of the present invention can be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. For tablets for oral use, commonly used carriers include lactose and cornstarch. Lubricants such as magnesium stearate are also usually added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. When an aqueous suspension is required for oral use, the active ingredient is mixed with an emulsifying and suspending agent. If desired, certain sweeteners, flavorings, or colorings can also be added.

[0376] Alternatively, the pharmaceutically acceptable compositions of the present invention may be administered in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore can melt in the rectum or vaginal cavity to release the drug. Such materials include cocoa butter, polyethylene glycol, or suppository waxes that are solid at ambient temperature but liquid at body temperature, and therefore can melt in the rectum or vaginal cavity to release the active compound.

[0377] The pharmaceutically acceptable compositions of the present invention may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0378] Topical application for the lower intestinal tract may be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0379] For topical application, the pharmaceutically acceptable composition can be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable composition can be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0380] For ophthalmic use, pharmaceutically acceptable compositions may be prepared, for example, in an isotonic solution of 100 mg of ophthalmic solution, with or without preservatives, such as benzylalkonium chloride. The compositions may be formulated as a micronized suspension in pH-adjusted sterile saline or other aqueous solution, or preferably as a solution in isotonic, pH-adjusted sterile saline or other aqueous solution. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum. The pharmaceutically acceptable compositions of the present invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical formulation art and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0381] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, seasonings, and fragrances.

[0382]

[0356] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid can be used in the preparation of injectables.

[0383]

[0357] Injectable preparations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0384] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound depends, in turn, on its rate of dissolution, which in turn depends on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0385] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is dispersed in at least one inert pharmaceutically acceptable excipient or carrier (e.g., sodium citrate or dicalcium phosphate), and / or a) fillers or extenders (e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid), b) binders (e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia), c) humectants (e.g., glycerol), d) disintegrants (e.g., agar, calcium carbonate, , potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate), e) solution retarders (e.g., paraffin), f) absorption accelerators (e.g., quaternary ammonium compounds), g) wetting agents (e.g., cetyl alcohol and glycerol monostearate, h) absorbents (e.g., kaolin and bentonite clay), and i) lubricants (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof). In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0386]

[0360] Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols, etc. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. Solid dosage forms may optionally contain opacifying agents. These solid dosage forms can also be composed to release the active ingredient only, or preferentially, in a certain part of the intestinal tract, optionally with a delayed release. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols, etc.

[0387] The active compound may also be in microencapsulated form with one or more of the excipients described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. These dosage forms may also contain, as is common practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents, and may have compositions that release the active ingredient only, or preferentially, in a certain part of the intestinal tract, optionally with a delay. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0388] Dosage forms for topical or transdermal administration of a compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers, as required. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the present invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound into the body. Such dosage forms can be made by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0389] The compounds of the present invention are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. As used herein, the phrase "unit dosage form" refers to a physically discrete unit of pharmaceutical agent appropriate for the patient being treated. However, it will be understood that the total daily usage of the compounds and compositions of the present invention may be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex, and dietary habits; the administration time, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination or concomitantly with the specific compound used, and similar factors well known in the medical field.

[0390] The amount of the compounds of the present invention that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the particular mode of administration, and other factors. Preferably, the compositions should be formulated so that a patient receiving these compositions can receive a dosage of between 0.01 and 100 mg / kg body weight / day of the inhibitor.

[0391] Depending on the particular condition, or disease, to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent that condition, may also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease or condition are known as "appropriate for the disease, or condition, being treated."

[0392] For example, chemotherapeutic agents or other anti-proliferative agents can be combined with the compounds of the present invention to treat proliferative diseases and cancer. Examples of known chemotherapeutic agents include PI3K inhibitors (e.g., idelalisib and copanlisib), BCL-2 inhibitors (e.g., venetoclax), BTK inhibitors (e.g., ibrutinib and acalabrutinib), etoposide, CD20 antibodies (e.g., rituximab, ocrelizumab, obinutuzumab, ofatumumab, ibritumomab tiuxetan, tositumomab, and ublituximab), aretuzumab (aletuzumab), and the like. ), bendamustine, cladribine, doxorubicin, chlorambucil, prednisone, midostaurin, lenalidomide, pomalidomide, checkpoint inhibitors (e.g., ipilimumab, nivolumab, pembolizumab, atezolizumab, avelumab, durvalumab), engineered cell therapy (e.g., CAR-T therapy - Kymriah®, Yescarta®), Gleevec TM , adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferon, and platinum derivatives.

[0393]

[0367] And, in some instances, radiation therapy is administered during the course of treatment in which a compound of the present invention (or a pharmaceutically acceptable salt thereof) is administered to a patient in need thereof.

[0394] Other examples of drugs that can be used in combination with the inhibitors of the present invention include, but are not limited to, the following: drugs for the treatment of Alzheimer's disease, such as Aricept® and Excelon®; L-DOPA / carbidopa, entacapone, ropinrole, Parkinson's disease treatments such as pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; beta interferons (e.g., Avonex® and Rebif®), Copaxone®, and mitoxane drugs for the treatment of multiple sclerosis (MS), such as entrone; albuterol and Singulair (registered trademark); drugs for the treatment of asthma, such as fluticasone; drugs for the treatment of schizophrenia, such as Zyprexa, Risperdal, Seroquel, and haloperidol; anti-inflammatory drugs, such as corticosteroids, TNF blockers, IL-1RA, azathioprine, cyclophosphamide, and sulfasalazine; cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine. Immunomodulatory and immunosuppressive drugs such as rufasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and antiparkinsonian drugs; drugs for the treatment of cardiovascular disease such as beta blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; drugs for the treatment of liver disease such as corticosteroids, cholestyramine, interferons, and antivirals; drugs for the treatment of blood disorders such as corticosteroids, anti-leukemia drugs, and growth factors; and drugs for the treatment of immune deficiency disorders such as gamma globulin.

[0395] The amount of additional therapeutic agent present in the compositions of the invention will not exceed the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions disclosed herein will be in the range of about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0396] B. Uses of the Compounds and Compositions The bifunctional compounds of the present invention are useful for degrading BTK in biological samples or patients via the ubiquitin proteolytic pathway. Accordingly, embodiments of the present invention provide methods for treating a BTK-mediated disease or disorder. As used herein, the term "BTK-mediated disease or disorder" refers to any disease, disorder, or other deleterious condition in which BTK is known to play a role. In certain instances, the BTK-mediated disease or disorder is a proliferative disorder or an autoimmune disorder. Examples of proliferative disorders include cancer.

[0397] The term "cancer" includes, but is not limited to, the following cancers: epidermoid oral: buccal cavity, lips, tongue, mouth, pharynx; cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchogenic lung carcinoma (squamous cell or epidermoid, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitin hamartoma, mesothelioma; gastrointestinal: esophagus (squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small bowel or small intestine intestines) (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, large bowel or large intestines (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colorectal, colorectal Intestine, rectum; genitourinary system: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary tract; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma tumor, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochronfroma), benign chondroma, chondroblastoma, cartilage Bone myxofibroma, osteoid and giant cell tumor; Nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma; Gynecological system: uterus (endometrial carcinoma), cervix (cervical carcinoma, preneoplastic cervical dysplasia), ovary (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma), breast; blood system: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), hairy cell; lymphatic system disorders (e.g., mantle cell lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphoma, and follicular lymphoma); skin: malignant (malilymphgnant) melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, keratoacanthoma, moles dysplastic nevi, lipoma, hemangioma, Skin fibromas, keloids, psoriasis, thyroid gland: papillary thyroid carcinoma, follicular thyroid carcinoma; medullary thyroid carcinoma, anaplastic thyroid carcinoma, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid carcinoma, pheochromocytoma, paraganglioma; and adrenal gland: neuroblastoma.

[0398] Examples of autoimmune disorders include urticaria (urticaria), graft-versus-host disease, pemphigus vulgaris, achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, axonal and neuronal neuropathy (AMAN), Barrow's disease, Behcet's disease, Benign mucous membrane pemphigoid, bullous pemphigoid, Castleman's disease (CD), celiac disease, Chagas' disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosa Plaques, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's disease, hemolytic anemia, Henoch-Schönlein purpura (HSP), herpes gestationis or pemphigoid of gestationis (PG), hidradenitis suppurativa (HS) (acne inversa), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP) P), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, lignified conjunctivitis, linear immunoglobulin A disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Much-Habermann disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica,Neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatoid arthritis (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, type II, type III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progestational dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm and testicular autoimmunity, stiff-person syndrome These include subacute bacterial endocarditis (SPS), subacute bacterial endocarditis (SBE), Susac syndrome, sympathetic ophthalmia (SO), Takayasu's arteritis, temporal arteritis (giant cell arteritis), thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease, and Wegener's granulomatosis (or granulomatosis with polyangiitis (GPA)). [Example]

[0399] IV. Working Examples

[0375] Additional embodiments are disclosed in more detail in the following examples, which are not intended to limit the scope of the claims in any way.

[0400] Preliminary synthesis Step 1: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione A mixture of 5-fluoro-1,3-dihydro-2-benzofuran-1,3-dione (5.0 g, 30.10 mmol), 3-aminopiperidine-2,6-dione hydrochloride (6.9 g, 42.14 mmol), and NaOAc (4.2 g, 51.17 mmol) in HOAc (50 mL) was stirred at 120° C. for 5 hours and then concentrated in vacuo. The residue was washed with water, and the solid was collected by filtration. The crude product was washed twice with water and twice with ethyl acetate and dried to give 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (7.7 g, 92%) as a light brown solid. 1 H NMR(300MHz,DMSO-d6)δ11.16(s,1H),8.03-8.00(m,1H),7.87-7.85(m,1H),7.75-7.7 0(m,1H),5.19-5.15(m,1H),2.94-2.86(m,1H),2.63-2.48(m,2H),2.12-2.06(m,1H).F NMR(300MHz,DMSO-d6)δ-102.078.

[0401] Step 2: Amine substitution of aryl fluorides To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (1.0 g, 3.62 mmol) in N-methylpyrrolidone (10 mL) was added amine (3.60 mmol) and DIEA (1.4 g, 10.83 mmol). The resulting solution was stirred at 80° C. for 16 hours. The reaction mixture was cooled to room temperature and purified by reverse-phase flash chromatography to give the corresponding final product.

[0402] Step 3: Oxidation of the alcohol to an aldehyde To a mixture of the alcohol (1.06 mmol) in CH2Cl2 (10 mL) was added Dess-Martin periodinane (2.12 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was purified by column chromatography to give the desired aldehyde.

[0403] Example 1: Synthesis of 5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]-3-{[4-(piperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide Step 1: tert-Butyl (3R)-3-{[(2-chloroethyl)carbamoyl]amino}piperidine-1-carboxylate [ka] To a mixture of tert-butyl (3R)-3-aminopiperidine-1-carboxylate (25.0 g, 125 mmol) and triethylamine (34.8 mL, 25.3 g, 250 mmol) in DCM (250 mL) was added 1-chloro-2-isocyanatoethane (12.8 mL, 15.8 g, 150 mmol) over 25 minutes. A mild exotherm was observed. After 4 hours, 100 mL of water was added. The layers were separated. The organic layer was dried over Na2SO4 and concentrated. The mixture was dissolved in ethyl acetate and filtered through 1000 cc of silica gel in a 2000 mL Buchner funnel eluted with ethyl acetate. The resulting solution was concentrated in vacuo to give tert-butyl (3R)-3-{[(2-chloroethyl)carbamoyl]amino}piperidine-1-carboxylate (40.6 g, quantitative), which was used without further purification. LCMS: C 13 H 24 ClN3O3 theoretical value: 305, measured value: m / z = 306 [M+H] + .

[0404] Step 2: tert-Butyl (3R)-3-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate [ka] To an ice-cooled mixture of tert-butyl (3R)-3-{[(2-chloroethyl)carbamoyl]amino}piperidine-1-carboxylate (40.3 g, 132 mmol) in THF (400 mL) was added 60% sodium hydride (10.6 g, 264 mmol) in several portions. The cooling bath was melted, and the reaction was stirred at room temperature overnight. Another portion of 60% sodium hydride (5.65 g, 141 mmol) was added, and gas evolution occurred. A mild exotherm was observed over 10 minutes. After 2 hours, the reaction was quenched by the addition of 75 mL of water. The layers were separated. The aqueous layer was extracted twice with 50 mL of DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The resulting material was partitioned between acetonitrile and hexane. The acetonitrile layer was concentrated in vacuo to provide tert-butyl (3R)-3-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (33.9 g, 95.4%). LCMS: C 13 H 23 N3O3 theoretical value 269, measured value: m / z = 270 [M+H] + .

[0405] Step 3: tert-Butyl (3R)-3-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate [ka] To an ice-cooled mixture of tert-butyl (3R)-3-(2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (33.8 g, 126 mmol) in THF (300 mL) was added 60% sodium hydride (10.1 g, 251 mmol) in several portions. After 5 min, the cooling bath was removed and gas evolution was observed for 1 h. The mixture was cooled in an ice bath. Methyl iodide (11.7 mL, 26.7 g, 188 mmol) was added over 5 min. The cooling bath was allowed to expire. After stirring at room temperature for 16 h, the reaction was quenched with 75 mL of water. The layers were separated. The organic layer was washed with brine. The combined aqueous layer was extracted twice with DCM. The combined organic layer was dried over anhydrous Na2SO4 and concentrated. The resulting material was partitioned between acetonitrile and hexane. The acetonitrile layer was filtered and concentrated in vacuo to give tert-butyl (3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (38.4 g, quantitative), which was used directly without further purification. LCMS: C 14 H 25 N3O3 theoretical value 283, measured value: m / z = 306 [M+Na] + .

[0406] Step 4: 1-Methyl-3-[(3R)-piperidin-3-yl]imidazolidin-2-one hydrochloride [ka] tert-Butyl (3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (35.1 g, 124 mmol) was stirred in 4 M hydrogen chloride solution in dioxane (310 mL, 1.24 mol) for 2 hours. The mixture was concentrated in vacuo to give 1-methyl-3-[(3R)-piperidin-3-yl]imidazolidin-2-one hydrochloride (35.0 g, quantitative), which was used directly without further purification. LCMS: C9H 17 NO theoretical value 183, measured value: m / z = 184 [M+H] + .

[0407] Step 5: 3-chloro-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carbonitrile [ka] 3,5-Dichloropyrazine-2-carbonitrile (21.6 g, 124 mmol) l) was added to an ice-cooled mixture of 1-methyl-3-[(3R)-piperidin-3-yl]imidazolidin-2-one hydrochloride (27.2 g, 124 mmol) and N,N-diisopropylethylamine (86.3 mL, 495 mmol) in DMF (300 mL). After 15 min, the cooling bath was removed. After stirring for 16 h, the mixture was diluted with 800 mL of water. The mixture was extracted with ethyl acetate. The organic layer was washed twice with water and once with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by flash chromatography on a 330 g silica gel column eluted with a 0-3% MeOH / DCM gradient to provide 3-chloro-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carbonitrile (22.1 g, 55.6%). LCMS: C14H17ClNO theoretical 320, observed: m / z=320 [M+H] + .

[0408] Step 6: tert-Butyl 4-[4-({3-cyano-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]piperazine-1-carboxylate [ka] 3-Chloro-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carbonitrile (9.57 g, 29.8 mmol), tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (8.27 g, 29.8 mmol), and cesium carbonate (29.2 g, 89.5 mmol) were placed in a 200 mL round-bottom flask containing dioxane (75 mL). The flask was evacuated until the mixture began to bubble, and the headspace was backfilled with argon for five cycles. BINAP (1.86 g, 2.98 mmol) and palladium(II) acetate (670 mg, 2.98 mmol) were added. The flask was evacuated and the headspace was backfilled with argon for five cycles. The mixture was heated at 100° C. for 3 hours. The mixture was filtered. The solid was washed with DCM. The resulting solution was concentrated in vacuo. The crude residue was purified by flash chromatography on a 330 g silica gel column eluted with a 0-5% MeOH / DCM gradient to provide tert-butyl 4-[4-({3-cyano-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]piperazine-1-carboxylate (8.81 g, 52.6%). LCMS: C 29 H 39 N9O3 theoretical value 561, measured value: m / z = 584 [M+Na] + .

[0409] Step 7: tert-Butyl 4-[4-({3-carbamoyl-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]piperazine-1-carboxylate [ka] To a homogeneous solution of tert-butyl 4-[4-({3-cyano-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]piperazine-1-carboxylate (8.23 g, 14.7 mmol) in DMSO (80 mL) and MeOH (160 mL) was added cesium carbonate (4.77 g, 14.7 mmol). The mixture was cooled in an ice bath. A 30% solution of hydrogen peroxide (22.0 mL, 213 mmol) was added in two portions. After 5 minutes, the ice bath was removed. After 2 hours at room temperature, the mixture was cooled in an ice bath. 70 mL of acetonitrile was added. The ice bath was removed. After 15 minutes, the volatiles were removed in vacuo and the mixture was diluted with 1 L of ethyl acetate. The mixture was washed with three portions of water, then brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by flash chromatography on a 220 g silica gel column eluted with a 0-10% MeOH / EtOAc gradient to provide tert-butyl 4-[4-({3-carbamoyl-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]piperazine-1-carboxylate (7.23 g, 85.1%). LCMS: C 29 H 41 N9O4 theoretical value 579, measured value m / z = 580 [M+H] + .

[0410] Step 8: 5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]-3-{[4-(piperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide trifluoroacetate [ka] tert-Butyl 4-[4-({3-carbamoyl-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]piperazine-1-carboxylate (2.65 g, 4.5 7 mmol) was stirred in DCM (15 mL) and TFA (15 mL). After 30 min, the mixture was concentrated to provide 5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]-3-{[4-(piperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide trifluoroacetate (2.71 g, 100%). LCMS: C 24 H 33 N9O2 theoretical value 479, measured value m / z = 480 [M+H] + .

[0411] Step 9: tert-Butyl 4-[4-({3-cyano-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]piperidine-1-carboxylate [ka] A mixture of 3-chloro-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carbonitrile (244 mg, 0.76 mmol), tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (211 mg, 0.76 mmol), Pd(OAc) (56.4 mg, 0.25 mmol), BINAP (156.3 mg, 0.25 mmol), and CsCO (7434 mg, 2.28 mmol) was degassed and backfilled with N five times. The mixture was stirred at 100 °C for 90 min. The mixture was filtered through Celite, washed with MeOH / EtOAc, concentrated, and purified by MPLC (0-100% EtOAc in CHCl) to give tert-butyl 4-[4-({3-cyano-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]piperidine-1-carboxylate (259 mg, 60.7%). LCMS: C 30 H 40 N8O3 theoretical value 560, measured value m / z = 561 [M+H] + .

[0412] Step 10: tert-Butyl 4-[4-({3-carbamoyl-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]piperidine-1-carboxylate [ka] H2O2 (30% in water, 2.50 mL, 0.24 mmol) was added to a mixture of tert-butyl 4-[4-({3-cyano-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]piperidine-1-carboxylate (259 mg, 0.46 mmol), Cs2CO3 (150.5 mg, 0.46 mmol), MeOH (9 mL), and DMSO (0.5 mL). The mixture was stirred at room temperature for 30 min. The mixture was concentrated, EtOAc was added, and the organic phase was washed with H2O and brine. The organic layer was dried over MgSO, filtered, concentrated, and purified by MPLC (0-10% MeOH in CHCl) to give tert-butyl 4-[4-({3-carbamoyl-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]piperidine-1-carboxylate (252 mg, 94%). LCMS: C 30 H 42 N8O4 theoretical value 578, measured value m / z = 579 [M+H] + .

[0413] Step 11: 5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]-3-{[4-(piperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide [ka] A mixture of tert-butyl 4-[4-({3-carbamoyl-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]piperidine-1-carboxylate (252 mg, 0.44 mmol), hydrogen chloride (4 M in dioxane, 2.72 mL, 10.89 mmol), and THF (2 mL) was stirred at room temperature for 2 hours. The volatiles were removed to give 5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]-3-{[4-(piperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide (209 mg, quantitative).

[0414] Example 2: 5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]-3-{[4-(4-methylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide Step 1: Ethyl 4-hydroxy-4-methylpiperidine-1-carboxylate [ka] A solution of ethyl 4-oxopiperidine-1-carboxylate (10.00 g, 58.41 mmol) in diethyl ether (100.00 mL) was cooled to −30° C., and chloro(methyl)magnesium (23.40 mL, 5.24 g, 70.10 mmol) (3 M solution in THF) was added. The resulting mixture was stirred at 0° C. for 2 h, and TLC showed no starting material. The reaction was quenched with 50 mL of ammonium chloride solution, and a white solid precipitated. The solid was filtered and washed with DCM. The aqueous layer of the combined solution was separated and washed twice with DCM. The combined organic solution was dried over Na2SO4 and concentrated. The crude product was purified by ISCO silica gel column (40 g) using 0-100% EtOAc / hexanes. Ethyl 4-hydroxy-4-methylpiperidine-1-carboxylate (8.7 g, 79.5% yield) was isolated. 1H NMR (500 MHz, chloroform-d) δ 4.13 (q, J = 7.1 Hz, 2H), 3.78 (s, 2H), 3.28 (dt, J = 14.2, 7.6 Hz, 2H), 1.56 (d, J = 5.3 Hz, 4H), 1.29-1.22 (m, 6H).

[0415] Step 2: Ethyl 4-(4-bromophenyl)-4-methylpiperidine-1-carboxylate [ka] Ethyl 4-hydroxy-4-methylpiperidine-1-carboxylate (3.08 g, 16.45 mmol) in bromobenzene (25.83 g, 164.50 mmol) was cooled to 0 °C, and trifluoromethanesulfonic acid (24.69 g, 164.50 mmol) was added. The resulting mixture was stirred at room temperature for 3 h. The solution was poured into ice, made basic with 1 N NaOH solution, and extracted three times with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The crude oil was purified on an ISCO silica gel column (40 g) using EtOAc / hexanes (0-50%) to give ethyl 4-(4-bromophenyl)-4-methylpiperidine-1-carboxylate (4.3 g, 80.1% yield). 1 H NMR (500 MHz, chloroform-d) δ 7.48-7.43 (m, 2H), 7.23-7.17(m,2H),4.12(q,J=7.1Hz,2H),3.56-3.48(m,2H),3.46-3.38(m,2H),2.03(br,2H),1.68(br,2H),1.28-1.21(m,6H).LCMS:C 15 H 20 BrNO2 theoretical value: 325, measured value: m / z = 326 [M+H] + .

[0416] Step 3: 4-(4-bromophenyl)-4-methylpiperidine [ka] To a solution of ethyl 4-(4-bromophenyl)-4-methylpiperidine-1-carboxylate (7.00 g, 21.46 mmol) in EtOH (75 mL) was added potassium hydroxide (24.08 g, 429.14 mmol) and the solution was heated at 80° C. overnight. LCMS showed no starting material remained. The solvent was evaporated under reduced pressure and the residue was dissolved in DCM (50 mL) and washed with water (20 mL). The aqueous layer was extracted with DCM (20 mL×5) and the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give 5.45 g of 4-(4-bromophenyl)-4-methylpiperidine as a crude product in quantitative yield, which was used directly in the next step without further purification. LCMS: C 12 H 16 BrN Theoretical value: 253, Measured value: m / z = 254 [M+H] + .

[0417] Step 4: tert-butyl 4-(4-bromophenyl)-4-methylpiperidine-1-carboxylate [ka] 4-(4-Bromophenyl)-4-methylpiperidine (5.40 g, 21.25 mmol) was dissolved in dichloromethane (75.00 mL), di-tert-butyl dicarbonate (7.42 g, 33.99 mmol) was added slowly, and the reaction was stirred at room temperature for 1 hour. The reaction solution was washed with water, followed by brine, dried over NaSO, and concentrated. ISCO silica gel column purification afforded tert-butyl 4-(4-bromophenyl)-4-methylpiperidine-1-carboxylate (7.4 g, 98.3% yield). 1H NMR (500MHz, chloroform-d) δ7.48-7.42(m,2H),7.27-7.16(m,2H),3.47(ddd,J=11.8,7.8,3.6H z,2H),3.41-3.33(m,2H),2.00(br,2H),1.71-1.62(m,2H),1.45(s,9H),1.23(s,3H)LCMS:C 12 H 16 BrN Theoretical value: 253, Measured value: m / z = 254 [M+H] + .

[0418] Step 5: tert-butyl 4-(4-aminophenyl)-4-methylpiperidine-1-carboxylate [ka] To a solution of tert-butyl 4-(4-bromophenyl)-4-methylpiperidine-1-carboxylate (2.60 g, 7.34 mmol), {[1,1'-biphenyl]-2-yl}dicyclohexylphosphane (65.00 mg, 0.19 mmol), Pd2(dba)3 (68.00 mg, 0.07 mmol), and LiHMDS (14.70 mL, 2.46 g, 14.68 mmol) in 15 mL of anhydrous THF was bubbled with nitrogen gas and stirred overnight at 65 °C under N2 protection. TLC showed no starting material remained. The reaction mixture was diluted with DCM, washed with water and brine, dried over Na2SO4, and concentrated. The crude product was purified by ISCO silica gel column using 0-60% EtOAc / hexanes to give tert-butyl 4-(4-aminophenyl)-4-methylpiperidine-1-carboxylate (1.42 g, 66.6% yield). 1 H NMR (500MHz, chloroform-d) δ7.14-7.08(m,2H),6.70-6.64(m,2H),3.58(s,2H),3.49-3.44(m ,2H),3.39-3.31(m,2H),2.00(br,2H),1.64-1.58(m,2H)1.45(s,9H),1.20(s,3H)LCMS:C 17 H 26N2O2 theoretical value: 290, measured value: m / z = 291 [M+H] + .

[0419] Step 6: tert-butyl 4-[4-({3-cyano-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]-4-methylpiperidine-1-carboxylate [ka]

[0418] A solution of tert-butyl 4-(4-aminophenyl)-4-methylpiperidine-1-carboxylate (0.64 g, 2.19 mmol), 3-chloro-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carbonitrile (0.61 g, 1.90 mmol), cesium carbonate (1.86 g, 5.70 mmol), palladium acetate (140.89 mg, 0.63 mmol), and [2'-(diphenylphosphanyl)-[1,1'-binaphthalen]-2-yl]diphenylphosphane BINAP (390.76 mg, 0.6 mmol) in 30 mL of dioxane was dissolved in 100 mL of toluene. Nitrogen gas was bubbled through the solution, which was then heated at 115°C under nitrogen protection for 2 hours. The reaction mixture was cooled to room temperature, diluted with 250 mL of EtOAc, and filtered. The filtrate was concentrated and purified on an ISCO silica gel column using EtOAc / DCM (0-100%) to give tert-butyl 4-[4-({3-cyano-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]-4-methylpiperidine-1-carboxylate (1.09 g, 100% yield). LCMS: C 31 H 42 N8O3 theoretical value: 574, measured value: m / z = 575 [M+H] + .

[0420] Step 7: tert-butyl 4-[4-({3-carbamoyl-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]-4-methylpiperidine-1-carboxylate [ka] tert-Butyl 4-[4-({3-cyano-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]-4-methylpiperidine-1-carboxylate (1.09 g, 1.9 mmol) was dissolved in methanol (25.00 mL) and DMSO (5.00 mL), and cesium carbonate (325 mg, 1.0 mmol) was added, followed by 30% H2O2 solution (2.31 g, 3 mL, 20.36 mmol). Stirred at room temperature for 30 minutes. LCMS showed no starting material remained. 10 mL of acetonitrile was added, stirred for 5 minutes, and the solvent was evaporated completely. The residue was dissolved in 200 mL of EtOAc, washed three times with water, dried over Na2SO4, and concentrated. Purification on an ISCO silica gel column (24 g) using 30–100% EtOAc / hexanes followed by 0–10% MeOH / DCM afforded tert-butyl 4-[4-({3-carbamoyl-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]-4-methylpiperidine-1-carboxylate (1.00 g, 82.9% yield). 1H NMR(500MHz,chloroform-d)δ10.84(s,1H),7.60(d,J=8.8Hz,2H),7.49(s,1H),7.26(d,J=8.8Hz,2H),5.18(s,1H),4.36(t,J=11.6Hz,2H) ),3.81(m,1H),3.49(br,2H),3.43-3.26(m,5H),3.08(t,J=11.7Hz,1H),2.98-2.92(m,1H),2.82(s,3H),2.05(d,J=9.1Hz,2H),2.02- 1.97(m,1H),1.90(dt,J=13.3,3.3Hz,1H),1.76(td,J=11.7,3.5Hz,1H),1.82-1.65(m,3H),1.45(s,9H),1.25(s,3H).LCMS:C 31 H 44 N8O4 theoretical value: 592, measured value: m / z = 593 [M+H] + .

[0421] Step 8: 5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]-3-{[4-(4-methylpiperidin-4-yl)phenyl ]amino}pyrazine-2-carboxamide [ka]

[0422] tert-Butyl 4-[4-({3-carbamoyl-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]-4-methylpiperidine-1-carboxylate (200.00 mg, 0.34 mmol) was dissolved in 4N HCl in dioxane (2 mL) and stirred at room temperature for 30 minutes. The solvent was evaporated to give 5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]-3-{[4-(4-methylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide as a crude product in quantitative yield, which was used directly in the next step without further purification. LCMS: C 26 H 36N8O2 theoretical value: 492, measured value: m / z = 493 [M+H] + .

[0422] Example 3: Synthesis of 3-{[4-(azetidin-3-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide Step 1: tert-butyl 3-[4-({3-cyano-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]azetidine-1-carboxylate [ka]

[0425] 3-Chloro-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carbonitrile (207 mg, 0.65 mmol), tert-butyl 3-(4-aminophenyl)azetidine-1-carboxylate (160 mg, 0.65 mmol), and cesium carbonate (847 mg, 2.60 mmol) were placed in a vial containing dioxane (5 mL). The vial was evacuated until the mixture bubbled, and the headspace was backfilled with argon for five cycles. BINAP (80.4 mg, 0.13 mmol) and palladium(II) acetate (29.0 mg, 0.13 mmol) were added. The vial was evacuated and the headspace was backfilled with argon. The space was backfilled with argon for five cycles. The mixture was heated at 90° C. overnight. The mixture was diluted with water and extracted twice with DCM. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by flash chromatography on a 24 g silica gel column eluted with a 0-10% MeOH / ethyl acetate gradient to provide tert-butyl 3-[4-({3-cyano-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]azetidine-1-carboxylate (257 mg, 74.8%). LCMS: C 28 H 36 N8O3 theoretical value 532, measured value: m / z = 533 [M+H] + .

[0423] Step 2: tert-butyl 3-[4-({3-carbamoyl-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]azetidine-1-carboxylate [ka]

[0427] tert-Butyl 3-[4-({3-cyano-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]azetidine-1-carboxylate (257 mg, 0.48 mmol) was dissolved in MeOH (6 mL) and DMSO (3 mL). Cesium carbonate (157 mg, 0.48 mmol) was added, followed by 1.5 mL of 35% HO. After 3 h, 4 mL of ACN was added. After 20 min, the mixture was diluted with ethyl acetate and washed three times with water. The organic layer was dried over NaSO and concentrated in vacuo. The crude residue was purified by flash chromatography on a 24 g silica gel column eluted with a 0-10% MeOH / ethyl acetate gradient to provide tert-butyl 3-[4-({3-carbamoyl-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]azetidine-1-carboxylate (261 mg, 98.2%). LCMS: C 28 H 38 N8O4 theoretical value 550, measured value m / z = 551 [M+H] + .

[0424] Step 3: 3-{[4-(azetidin-3-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide [ka]

[0429] tert-Butyl 3-[4-({3-carbamoyl-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]azetidine-1-carboxylate (261.00 mg, 0.47 mmol) was stirred in DCM (1 mL) and TFA (1 mL) for 15 minutes, concentrated in vacuo, and then lyophilized to provide 3-{[4-(azetidin-3-yl)phenyl]amino}-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide (265 mg, 100%). LCMS: C 23 H 30 N8O2 theoretical value 451, measured value: m / z = 451 [M+H] + .

[0425] Example 4 Synthesis of (R)-3-((4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide [ka] Step 1: tert-Butyl 6-(4-nitrophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0432] A mixture of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (515 mg, 2.60 mmol), MeCN (2 mL), ethylbis(propan-2-yl)amine (1.81 mL, 10.4 mmol), and 4-fluoronitrobenzene (367 mg, 2.60 mmol) was stirred at 60 °C for 4 h. EtOAc and H2O were added. The organic layer was dried over MgSO4, filtered, concentrated, and purified by MPLC (0-50% EtOAc in hexanes) to give tert-butyl 6-(4-nitrophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (491 mg, 59.2%). LCMS: C 16 H 21N3O4 theoretical value: 319, measured value: m / z = 320 [M+H] + .

[0426] Step 2: tert-Butyl 6-(4-aminophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0434] A mixture of Pd / C (16 mg, 0.15 mmol), EtOH (15 mL), and tert-butyl 6-(4-nitrophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (491 mg, 1.54 mmol) was evacuated and backfilled with H five times. The mixture was stirred at room temperature for 2 h. The mixture was filtered through Celite, washed with EtOAc / MeOH, and concentrated to give tert-butyl 6-(4-aminophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (439 mg, 98.7%). LCMS: C 16 H 23 N3O2 theoretical value 289, measured value: m / z = 2 90[M+H] + .

[0427] Step 3: tert-Butyl (R)-6-(4-((3-cyano-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0436] A mixture of tert-butyl 6-(4-aminophenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (245 mg, 0.85 mmol), 3-chloro-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carbonitrile (272 mg, 0.85 mmol), Pd(OAc) (62.8 mg, 0.28 mmol), [2'-(diphenylphosphanyl)-[1,1'-binaphthalen]-2-yl]diphenylphosphane (174 mg, 0.28 mmol), and cesium carbonate (829 mg, 2.54 mmol) was degassed and backfilled with N five times. Dioxane (4 mL) was added. The mixture was stirred at 100 °C for 90 min. The mixture was filtered through Celite, washed with MeOH / EtOAc, concentrated, and purified by MPLC (0-100% EtOAc in CHCl) to give tert-butyl 6-[4-({3-cyano-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (272 mg, 55.9%). LCMS: C 30 H 39 N9O3 theoretical value 573, measured value: m / z = 574 [M+H] + .

[0428] Step 4: tert-Butyl (R)-6-(4-((3-carbamoyl-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0438] HO (30% in HO, 0.80 mL, 0.08 mmol) was added to a mixture of tert-butyl 6-[4-({3-cyano-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (272 mg, 0.47 mmol), cesium carbonate (154 mg, 0.47 mmol), MeOH (10 mL), and DMSO (0.5 mL). The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated. EtOAc was added, and the organic phase was washed with HO and brine. The organic layer was dried over MgSO, filtered, concentrated, and purified by MPLC (0-10% MeOH in CHCl) to give tert-butyl 6-[4-({3-carbamoyl-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (142 mg, 50.6%). LCMS: C 30 H 41 N9O4 theoretical value 591, measured value: m / z = 592 [M+H] + .

[0429] Step 5: (R)-3-((4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

[0440] A mixture of tert-butyl 6-[4-({3-carbamoyl-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (142 mg, 0.24 mmol), CHCl (2 mL), and TFA (0.4 mL) was stirred at room temperature for 1 hour. The volatiles were removed to give 3-[(4-{2,6-diazaspiro[3.3]heptan-2-yl}phenyl)amino]-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl] Pyrazine-2-carboxamide (117 mg, 99.2%) was obtained. LCMS: C 25 H 33 N9O2 theoretical value 491, measured value: m / z = 492 [M+H] + .

[0430] Example 5 Synthesis of (R)-3-((4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide [ka] Step 1: tert-Butyl 9-(4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[0443] A mixture of 4-fluoronitrobenzene (554.7 mg, 3.93 mmol), DMF (20 mL), ethyl bis(propan-2-yl)amine (2.74 mL, 15.7 mmol), and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (1000 mg, 3.93 mmol) was stirred at 90 °C overnight. EtOAc and H2O were added. The organic layer was dried over MgSO4, filtered, concentrated, and purified by MPLC (0-50% EtOAc in hexanes) to give tert-butyl 9-(4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (1287.00 mg, 87.2%). 20 H 29 N3O4 theoretical value: 375, measured value: m / z = 376 [M+H] + .

[0431] Step 2: tert-Butyl 9-(4-aminophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[0445] A mixture of tert-butyl 9-(4-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (1.29 g, 3.43 mmol), Pd / C (36 mg, 0.34 mmol), and EtOH (30 mL) was evacuated and backfilled with H 5 times. The mixture was stirred at room temperature for 2 hours. The mixture was filtered through Celite. Washing with EtOAc / MeOH and concentration gave tert-butyl 9-(4-aminophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (871 mg, 73.5%). LCMS: C 20 H 31 N3O2 theoretical value: 345, measured value: m / z = 346 [M+H] + .

[0432] Step 3: tert-Butyl (R)-9-(4-((3-cyano-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[0447] A mixture of tert-butyl 9-(4-aminophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (162.6 mg, 0.47 mmol), 3-chloro-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carbonitrile (151 mg, 0.47 mmol), Pd(OAc) (34.9 mg, 0.16 mmol), [2'-(diphenylphosphanyl)-[1,1'-binaphthalen]-2-yl]diphenylphosphane (96.7 mg, 0.16 mmol), and cesium carbonate (460 mg, 1.41 mmol) was degassed and backfilled with N five times. The mixture was stirred at 100 °C for 90 min. The mixture was filtered through Celite, washed with MeOH / EtOAc, concentrated, and purified by MPLC (0-100% EtOAc in CHCl) to give tert-butyl 9-[4-({3-cyano-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (204 mg, 68.8%). LCMS: C 34 H 47 N9O3 theoretical value 629, measured value: m / z = 630 [M+H] + .

[0433] Step 4: tert-Butyl (R)-9-(4-((3-carbamoyl-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[0449] HO (30% in HO, 0.55 mL, 0.00 g, 0.05 mmol) was added to a mixture of tert-butyl 9-[4-({3-cyano-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (204 mg, 0.32 mmol), cesium carbonate (106 mg, 0.32 mmol), MeOH (6 mL), and DMSO (0.3 mL). The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated. EtOAc was added, and the organic phase was washed with HO and brine. The organic layer was dried over MgSO, filtered, concentrated, and purified by MPLC (0-10% MeOH in CHCl) to give tert-butyl 9-[4-({3-carbamoyl-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (95.00 mg, 45%). LCMS: C 34 H 49 N9O4 theoretical value 647, measured value: m / z = 648 [M+H] + .

[0434] Step 5: (R)-3-((4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

[0451] A mixture of tert-butyl 9-[4-({3-carbamoyl-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)phenyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (25 mg, 0.04 mmol), CHCl (1 mL), and TFA (0.2 mL) was stirred at room temperature for 1 h. The volatiles were removed to give 3-[(4-{3 ,9-diazaspiro[5.5]undecan-3-yl}phenyl)amino]-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carboxamide (21.00 mg, 99.4%) was obtained. LCMS: C 29 H 41 N9O2 theoretical value 547, measured value: m / z = 548 [M+H] + .

[0435] Example 6 Synthesis of (R)-3-((4-(2,9-diazaspiro[5.5]undecan-9-yl)phenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide [ka] Step 1: tert-Butyl 9-(4-nitrophenyl)-2,9-diazaspiro[5.5]undecane-2-carboxylate

[0454] Para-fluoronitrobenzene (1 equivalent) and spirocyclic amine (1 equivalent) were combined in DMF, followed by the addition of potassium carbonate (2 equivalents). The reaction mixture was stirred at 65°C for 5 hours and then cooled to room temperature. The reaction mixture was then partitioned between ethyl acetate and water, and the organic layer was separated, dried over magnesium sulfate, and filtered. The solution was concentrated to give tert-butyl 9-(4-nitrophenyl)-2,9-diazaspiro[5.5]undecane-2-carboxylate. LCMS C 20 H 29 N3O4 theoretical value: 375.5, measured value: m / z = 376.6 [M+H] + .

[0436] Step 2: tert-Butyl 9-(4-aminophenyl)-2,9-diazaspiro[5.5]undecane-2-carboxylate

[0456] The crude material from Step 1 of this Example 6 was dissolved in ethanol and water (10:1). Ammonium chloride (3.5 equiv.) and iron (3 equiv.) were added followed by vigorous stirring and heating at 90°C for 4 hours. The reaction was then filtered through Celite while still hot, and the Celite was washed with additional ethyl acetate. The resulting solution was partitioned between ethyl acetate and water. The aqueous layer was separated and re-extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated. Silica gel chromatography revealed the tert-butyl 2-methylpropional product. 9-(4-aminophenyl)-2,9-diazaspiro[5.5]undecane-2-carboxylate (52% over two steps). LCMS C 20 H 31 N3O2 theoretical value: 345.59, measured value: m / z = 346.5 [M+H] + .

[0437] Step 3: tert-Butyl (R)-9-(4-((3-cyano-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)-2,9-diazaspiro[5.5]undecane-2-carboxylate

[0458] The chloropyrimidine intermediate (R)-3-chloro-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carbonitrile, tert-butyl 9-(4-aminophenyl)-2,9-diazaspiro[5.5]undecane-2-carboxylate, Pd(OAc) (0.15 equiv.), BINAP (0.15 equiv.), and cesium carbonate (2 equiv.) were combined in a microwave tube, followed by the addition of dioxane (0.25 M). Nitrogen was bubbled thoroughly for 30 seconds and then the tube was capped. The tube was heated to 90 °C and maintained at that temperature for 3 hours to give a dark reaction mixture, which was monitored by LCMS. The reaction was then cooled, filtered through Celite, and washed with ethyl acetate / methanol. The crude material was loaded onto silica and chromatographed (silica, 0-10% methanol in DCM) to provide tert-butyl (R)-9-(4-((3-cyano-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)-2,9-diazaspiro[5.5]undecane-2-carboxylate (40%). LCMS C 34 H 47 N9O3 theoretical value: 629.81, measured value: m / z = 630.7 [M+H] + .

[0438] Step 4: tert-Butyl (R)-9-(4-((3-carbamoyl-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)-2,9-diazaspiro[5.5]undecane-2-carboxylate

[0460] This material was then dissolved in methanol / DMSO (10:1) and NaOH pellets were added. The reaction was stirred for 5 minutes, after which a 35% solution of peroxide (2 mL of solution per mmol of reactant) was added. The reaction mixture was stirred for 3 hours and then partitioned between ethyl acetate and water. The organic layer was separated and dried over magnesium sulfate. Chromatography (0-10% methanol in DCM) provided (R)-3-((4-(2,9-diazaspiro[5.5]undecan-9-yl)phenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide (90% yield). LCMS C 34 H 49 N9O4 theoretical value: 647.8, measured value: m / z = 648.7 [M+H] + .

[0439] Step 5: (R)-3-((4-(2,9-diazaspiro[5.5]undecan-9-yl)phenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

[0462] (R)-3-((4-(2,9-diazaspiro[5.5]undecan-9-yl)phenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide was dissolved in DCM:TFA (5:1 ratio, 0.2 M) and the reaction was stirred for 4 hours. The reaction mixture was concentrated by rotary evaporation and then suspended in diethyl ether. The suspension was sonicated, then concentrated by rotary evaporation and further dried for 16 hours to give (R)-3-((4-(2,9-diazaspiro[5.5]undecan-9-yl)phenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide. LCMS C 29 H 41 N9O2 theoretical value: 547.7, measured value: m / z = 548.6 [M+H] + .

[0440] Example 7: Synthesis of (R)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-3-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrazine-2-carboxamide [ka] Step 1: tert-Butyl (R)-6-((3-cyano-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0465] (R)-3-chloro-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carbonitrile, aniline, Pd(OAc) (0.15 equiv.), BINAP (0.15 equiv.), and cesium carbonate (2 equiv.) were combined in a microwave tube, followed by the addition of dioxane (0.25 M). Nitrogen was bubbled thoroughly for 30 seconds and then the tube was capped. The tube was heated to 90° C. and maintained at that temperature for 3 hours to give a dark reaction mixture, which was monitored by LCMS. The reaction was then cooled, filtered through Celite, and washed with ethyl acetate / methanol. The crude material was loaded onto silica and chromatographed (silica, 0-10% methanol in DCM) to provide tert-butyl (R)-6-((3-cyano-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate. LCMS C 28 H 36 N8O3 Theoretical value: 532.7, Measured value: m / z = 533.5 [M+H] + .

[0441] Step 2: tert-Butyl (R)-6-((3-carbamoyl-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0467] tert-Butyl (R)-6-((3-cyano-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate was dissolved in methanol / DMSO (10:1) and NaOH pellets were added. The reaction was stirred for 5 minutes before adding 35% peroxide solution (2 mL of solution per mmol of reactant). The reaction mixture was stirred for 3 hours and then partitioned between ethyl acetate and water. The organic layer was separated and dried over magnesium sulfate. Chromatography (0-10% methanol in DCM) gave tert-butyl (R)-6-((3-carbamoyl-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino). )amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (18% over two steps). LCMS C 28 H 38 N8O4 theoretical value: 550.7, measured value: m / z = 551.7 [M+H] + .

[0442] Step 3: (R)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-3-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrazine-2-carboxamide

[0469] tert-Butyl (R)-6-((3-carbamoyl-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate was dissolved in DCM:TFA (5:1 ratio, 0.2 M) and the reaction was stirred for 4 hours. The reaction mixture was concentrated by rotary evaporation and then suspended in diethyl ether. The suspension was sonicated, then concentrated by rotary evaporation and dried for a further 16 hours before use in the next step. LCMS C 23 H 30 N8O2 theoretical value: 450.5, measured value: m / z = 451 [M+H]+ .

[0443] Example 8: Synthesis of (R)-3-((2-(azetidin-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide [ka] Step 1: tert-Butyl (R)-3-(6-((3-carbamoyl-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)azetidine-1-carboxylate

[0472] (R)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)-3-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrazine-2-carboxamide was combined with tert-butyl 3-oxoazetidine-1-carboxylate (1 equivalent) and stirred in a solution of DCE and TEA (10:1, 0.1 M) for 5 minutes. Sodium triacetoxyborohydride (5 equivalents) was then added and the reaction was stirred at room temperature for 5 hours. The reaction was then partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered and purified to give tert-butyl (R)-3-(6-((3-carbamoyl-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)-3 ,4-dihydroisoquinolin-2(1H)-yl)azetidine-1-carboxylate (yield 90%) was obtained. LCMS C 31 H 43 N9O4 theoretical value: 605, measured value: m / z = 606 [M+H] + .

[0444] Step 2: (R)-3-((2-(azetidin-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

[0474] tert-Butyl (R)-3-(6-((3-carbamoyl-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)azetidine-1-carboxylate was dissolved in DCM:TFA (5:1 ratio, 0.2 M) and the reaction was stirred for 4 hours. The reaction mixture was concentrated and then suspended in diethyl ether. The suspension was sonicated, then concentrated and dried for 16 hours to give (R)-3-((2-(azetidin-3-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide (95% yield). LCMS C 26 H 35 N9O2 theoretical value: 505, measured value: m / z = 506 [M+H] + .

[0445] Example 9: Synthesis of (R)-3-((4-(1-(azetidin-3-yl)piperidin-4-yl)phenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide [ka]

[0476] The amine intermediate was combined with tert-butyl 3-oxoazetidine-1-carboxylate (1 equivalent) and stirred in a solution of DCE and TEA (10:1, 0.1 M) for 5 minutes. Sodium triacetoxyborohydride (5 equivalents) was then added, and the reaction was stirred at room temperature for 5 hours. The reaction was then partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, then dried over magnesium sulfate and filtered. The crude intermediate was then dissolved in DCM:TFA (5:1 ratio, 0.2 M), and the reaction was stirred for 4 hours. The reaction mixture was concentrated by rotary evaporation and then suspended in diethyl ether. This suspension was sonicated, concentrated by rotary evaporation, and further dried for 16 hours to give tert-butyl 3-oxoazetidine-1-carboxylate (95% over two steps). LCMS C 41 H 47 N 11 O6 theoretical value: 789.9, measured value: m / z =790.7[M+H] + .

[0446] Example 10: Synthesis of (R)-3-((3-aminophenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide [ka] Step 1: tert-butyl (R)-(3-((3-cyano-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)carbamate

[0479] (R)-3-chloro-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carbonitrile, tert-butyl(3-aminophenyl)carbamate (1 equivalent), Pd(OAc)2 (0.15 equivalents), BINAP (0.15 equivalents), and cesium carbonate (2 equivalents) were combined in a microwave tube, followed by the addition of dioxane (0.25 M). Nitrogen was bubbled thoroughly for 30 seconds and then the tube was capped. The mixture was stirred at 90 °C for 3 hours. The reaction was then cooled, filtered through Celite, and washed with ethyl acetate / methanol. The crude material was purified by MPLC (0-10% MeOH in CH2Cl2) to give tert-butyl (R)-(3-((3-cyano-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)carbamate (45% yield). LCMS C 25 H 32 N8O3 theoretical value: 492.6, measured value: m / z = 493.6 [M+H] + .

[0447] Step 2: (R)-3-((3-aminophenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carbonitrile

[0481] tert-Butyl (R)-(3-((3-cyano-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)carbamate was dissolved in DCM:TFA (5:1 ratio, 0.2 M) and the reaction was stirred for 4 hours. The reaction mixture was concentrated by rotary evaporation and then suspended in diethyl ether. The suspension was sonicated, then concentrated by rotary evaporation and further dried for 16 hours to give (R)-3-((3-aminophenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carbonitrile (100% crude yield). LCMS C 20 H2 4N8O Theoretical value: 392.5, Measured value: m / z = 393.5 [M+H] + .

[0448] Step 3: (R)-3-((3-aminophenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

[0483] (R)-3-((3-aminophenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carbonitrile was dissolved in methanol / DMSO (10:1) and NaOH pellets were added. The reaction was stirred for 5 minutes, after which 35% peroxide solution (2 mL of solution per mmol of reactant) was added. The reaction mixture was stirred for 3 hours and then partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate, concentrated under vacuum, and purified by MPLC (0-10% methanol in DCM) to provide (R)-3-((3-aminophenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide. LCMS C 20 H 26 N8O2 theoretical value: 410.5, measured value: m / z = 411.5 [M+H] + .

[0449] Example 11: Synthesis of (R)-3-((4-(3-aminopropoxy)phenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide [ka] Step 1: tert-butyl (R)-(3-(4-((3-cyano-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)phenoxy)propyl)carbamate

[0486] (R)-3-chloro-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carbonitrile, tert-butyl(3-(4-aminophenoxy)propyl)carbamate (1 equivalent), Pd(OAc)2 (0.15 equivalents), BINAP (0.15 equivalents), and cesium carbonate (2 equivalents) were combined in a microwave tube, followed by the addition of dioxane (0.25 M). Nitrogen was bubbled thoroughly for 30 seconds and then the tube was capped. The mixture was stirred at 90 °C for 3 hours. The reaction was then cooled and filtered through Celite, rinsing with ethyl acetate / methanol. The crude material was purified by MPLC (0-10% MeOH in CH2Cl2) to give tert-butyl (R)-(3-(4-((3-cyano-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)phenoxy)propyl)carbamate (52% yield). LCMS C 28 H 38 N8O4 theoretical value: 550, measured value :m / z=551.7[M+H] + .

[0450] Step 2: (R)-3-((4-(3-aminopropoxy)phenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carbonitrile

[0488] tert-Butyl (R)-(3-(4-((3-cyano-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)phenoxy)propyl)carbamate was dissolved in DCM:TFA (5:1 ratio, 0.2 M) and the reaction was stirred for 4 hours. The reaction mixture was concentrated by rotary evaporation and then suspended in diethyl ether. The suspension was sonicated, then concentrated by rotary evaporation and further dried for 16 hours to give (R)-3-((4-(3-aminopropoxy)phenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carbonitrile (100% crude yield). LCMS C 23 H30 N8O2 theoretical value: 450.6, measured value: m / z = 451.6 [M+H] + .

[0451] Step 3: (R)-3-((4-(3-aminopropoxy)phenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide

[0490] (R)-3-((4-(3-aminopropoxy)phenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carbonitrile was dissolved in methanol / DMSO (10:1) and NaOH pellets were added. The reaction was stirred for 5 minutes, after which 35% peroxide solution (2 mL of solution per mmol of reactant) was added. The reaction mixture was stirred for 3 hours and then partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate, concentrated under vacuum, and purified by MPLC (0-10% methanol in DCM) to provide (R)-3-((4-(3-aminopropoxy)phenyl)amino)-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide (77% yield). LCMS C 23 H 32 N8O3 theoretical value: 468.6, measured value: m / z = 469.6 [M+H] + .

[0452] Example 12: General synthetic scheme for Examples 12A-12G [ka] Step 1: Formula P 1 Coupling of the nitrogen-containing ring to provide a compound of formula

[0493] In a typical synthesis, a mixture of 3,5-dichloropyrazine-2-carbonitrile (approximately 1 equivalent), a cyclic compound containing a ring nitrogen (approximately 1 equivalent), ethylbis(propan-2-yl)amine (approximately 2 equivalents), and a polar aprotic solvent such as DMF was stirred at room temperature for 2 hours. An organic solvent such as EtOAc was then added to the reaction mixture, which was then washed with water. The organic layer was dried over MgSO, filtered, concentrated, and purified by procedures such as crystallization or MPLC (0-100% EtOAc in hexanes) to give the purified product.

[0453] Step 2: Formula P 2 Coupling of aniline derivatives to provide compounds of formula

[0495] In a typical synthesis, 1 A mixture of the compound (approximately 1 equivalent), tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (approximately 1 equivalent), Pd(OAc) (approximately 0.3 equivalents), BINAP (approximately 0.3 equivalents), and CsCO (approximately 3 equivalents) was degassed and backfilled with N five times. The mixture was stirred at approximately 100°C for approximately 90 minutes. The mixture was filtered, for example, through Celite, and the cake was washed with a solvent system such as MeOH / EtOAc. The crude product was then concentrated and purified using techniques such as crystallization or MPLC.

[0454] Step 3: Expression P 3 Conversion of the cyano group to an acetamide to form a compound of formula

[0497] H2O2 (30% in water; approximately 0.17 equivalents) was added to a solution of formula P 2 (approximately 1 equivalent), Cs2CO3 (approximately 1 equivalent), and a 36:1 mixture of MeOH:DMSO as the solvent were added to the mixture. The mixture was stirred at room temperature for approximately 30 minutes. The mixture was concentrated, diluted with an organic solvent such as EtOAc, and the organic phase was washed with water and then brine. The organic layer was further dried over MgSO4, filtered, concentrated, and purified using techniques such as crystallization or MPLC.

[0455] Step 4: Formula P 4 Removal of the BOC group to provide the compound

[0499] In a typical synthesis, 3 The mixture of compounds was dissolved in a 2.5:1 mixture of 4M hydrogen chloride in dioxane to THF and stirred at room temperature for 2 hours. The volatiles were removed to give the product.

[0456] Example 12A: Synthesis of 3-((4-(piperazin-1-yl)phenyl)amino)-5-(piperidin-1-yl)pyrazine-2-carboxamide [ka] Step 1: 3-chloro-5-(piperidin-1-yl)pyrazine-2-carbonitrile

[0502] A mixture of 3,5-dichloropyrazine-2-carbonitrile (850 mg, 4.89 mmol), piperidine (0.48 mL, 4.89 mmol), ethylbis(propan-2-yl)amine (1.70 mL, 9.77 mmol), and DMF (20 mL) was stirred at room temperature for 2 hours. EtOAc and H2O were added. The organic layer was dried over MgSO4, filtered, concentrated, and purified by MPLC (0-100% EtOAc in hexanes) to give 3-chloro-5-(piperidin-1-yl)pyrazine-2-carbonitrile (1079.6 mg, 99.2%). LCMS: C 10 H 11 ClN4 theoretical value: 222, measured value: m / z = 223 [M+H] + .

[0457] Step 2: tert-butyl 4-(4-{[3-cyano-6-(piperidin-1-yl)pyrazin-2-yl]amino}phenyl)piperazine-1-carboxylate

[0504] A mixture of 3-chloro-5-(piperidin-1-yl)pyrazine-2-carbonitrile (534 mg, 2.40 mmol), tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (665 mg, 2.40 mmol), Pd(OAc) (177 mg, 0.79 mmol), BINAP (493 mg, 0.79 mmol), and CsCO (2345 mg, 7.20 mmol) was degassed and backfilled with N five times. The mixture was stirred at 100 °C for 90 min. The mixture was filtered through Celite, washed with MeOH / EtOAc, concentrated, and purified by MPLC (0-100% EtOAc in CH2Cl2) to give tert-butyl 4-(4-{[3-cyano-6-(piperidin-1-yl)pyrazin-2-yl]amino}phenyl)piperazine-1-carboxylate (833 mg, 74.9%). LCMS: C 25 H 33 N7O2 theoretical value: 463, measured value: m / z = 464 [M+H] + .

[0458] Step 3: tert-butyl 4-(4-((3-carbamoyl-6-(piperidin-1-yl)pyrazin-2-yl)amino)phenyl)piperazine-1-carboxylate

[0506] H2O2 (30% in water, 3.03 mL, 0.30 mmol) was added to a mixture of tert-butyl 4-(4-{[3-cyano-6-(piperidin-1-yl)pyrazin-2-yl]amino}phenyl)piperazine-1-carboxylate (833 mg, 1.80 mmol), Cs2CO3 (586 mg, 1.80 mmol), MeOH (35 mL), and DMSO (1 mL). The mixture was stirred at room temperature for 30 min. The mixture was concentrated. EtOAc was added, and the organic phase was washed with H2O and brine. The organic layer was dried over MgSO4. The residue was dried, filtered, concentrated, and purified by MPLC (0-10% MeOH in CH2Cl2) to give tert-butyl 4-(4-((3-carbamoyl-6-(piperidin-1-yl)pyrazin-2-yl)amino)phenyl)piperazine-1-carboxylate (809 mg, 93.5%). LCMS: C 25 H 35N7O3 theoretical value: 481, measured value: m / z = 482 [M+H] + .

[0459] Step 4: 3-{[4-(piperazin-1-yl)phenyl]amino}-5-(piperidin-1-yl)pyrazine-2-carboxamide

[0508] A mixture of tert-butyl 4-(4-{[3-carbamoyl-6-(piperidin-1-yl)pyrazin-2-yl]amino}phenyl)piperazine-1-carboxylate (20 mg, 0.04 mmol), hydrogen chloride (4 M in dioxane, 0.26 mL, 1.04 mmol), and THF (0.1 mL) was stirred at room temperature for 2 hours. The volatiles were removed to give 3-{[4-(piperazin-1-yl)phenyl]amino}-5-(piperidin-1-yl)pyrazine-2-carboxamide (15 mg, 95%). LCMS: C 20 H 27 NO theoretical value: 381, measured value: m / z = 382 [M+H] + .

[0460] Example 12B: Synthesis of (R)-5-(3-(hydroxymethyl)piperidin-1-yl)-3-((4-(piperidin-4-yl)phenyl)amino)pyrazine-2-carboxamide [ka]

[0510] Step 1: (R)-3-chloro-5-(3-(hydroxymethyl)piperidin-1-yl)pyrazine-2-carbonitrile using (R)-piperidin-3-ylmethanol as the amine. LCMS C 11 H 13 ClNO Theoretical value: 252 Measured value: m / z = 253 [M+H] + .

[0461]

[0511] Step 2: tert-Butyl (R)-4-(4-((3-cyano-6-(3-(hydroxymethyl)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)piperidine-1-carboxylate. LCMS: C27 H 36 N6O3 theoretical value: 492 Measured value: m / z = 493 [M+H] + .

[0462]

[0512] Step 3: tert-Butyl (R)-4-(4-((3-carbamoyl-6-(3-(hydroxymethyl)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)piperidine-1-carboxylate. LCMS C 27 H 38 N6O4 theoretical value: 510 Measured value: m / z = 511 [M+H] + .

[0463]

[0513] Step 4: (R)-5-(3-(hydroxymethyl)piperidin-1-yl)-3-((4-(piperidin-4-yl)phenyl)amino)pyrazine-2-carboxamide. LCMS C 22 H 30 N6O2 theoretical value: 410 Measured value: m / z = 411 [M+H] + .

[0464] Example 12C: 5-(4,4-difluoro-3-(hydroxymethyl)piperidine-1- Synthesis of (4-(piperidin-4-yl)phenyl)amino)pyrazine-2-carboxamide [ka]

[0515] Step 1: 3-chloro-5-(4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl)pyrazine-2-carbonitrile using (4,4-difluoropiperidin-3-yl)methanol as the amine. LCMS C 11 H 11 ClF2N4O Theoretical value: 288 Measured value: m / z = 289 [M+H] + .

[0465]

[0516] Step 2: tert-Butyl 4-(4-((3-cyano-6-(4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)piperidine-1-carboxylate. LCMS C 27 H 34 F2N6O3 theoretical value: 528 Measured value: m / z = 529 [M+H] + .

[0466]

[0517] Step 3: tert-Butyl 4-(4-((3-carbamoyl-6-(4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)piperidine-1-carboxylate. LCMS C 27 H 36 F2N6O4 theoretical value: 546 Measured value: m / z = 547 [M+H] + .

[0467]

[0518] Step 4: 5-(4,4-Difluoro-3-(hydroxymethyl)piperidin-1-yl)-3-((4-(piperidin-4-yl)phenyl)amino)pyrazine-2-carboxamide. LCMS C 22 H 28 F2N6O2 theoretical value: 446 Measured value: m / z = 447 [M+H] + .

[0468] Example 12D: Synthesis of 3-((4-(piperidin-4-yl)phenyl)amino)-5-(2-oxa-6-azaspiro[3.5]nonan-6-yl)pyrazine-2-carboxamide [ka]

[0520] Step 1: 3-chloro-5-(2-oxa-6-azaspiro[3.5]nonan-6-yl)pyrazine-2-carbonitrile using 2-oxa-6-azaspiro[3.5]nonane as the amine. LCMS C 12 H 13 ClNO Theoretical value: 264 Measured value: m / z = 265 [M+H] + .

[0469]

[0521] Step 2: tert-Butyl 4-(4-((3-cyano-6-(2-oxa-6-azaspiro[3.5]nonan-6-yl)pyrazin-2-yl)amino)phenyl)piperidine-1-carboxylate. LCMS C 28 H 36 N6O3 theoretical value: 504 Measured value: m / z = 505 [M+H] + .

[0470]

[0522] Step 3: tert-Butyl 4-(4-((3-carbamoyl-6-(2-oxa-6-azaspiro[3.5]nonan-6-yl)pyrazin-2-yl)amino)phenyl)piperidine-1-carboxylate. LCMS C 28 H 38 N6O4 theoretical value: 522 Measured value: m / z = 523 [M+H] + .

[0471]

[0523] Step 4: 3-((4-(piperidin-4-yl)phenyl)amino)-5-(2-oxa-6-azaspiro[3.5]nonan-6-yl)pyrazine-2-carboxamide. LCMS C 23 H 30 N6O2 theoretical value: 422 Measured value: m / z = 423 [M+H] + .

[0472] Example 12E: Synthesis of 3-((4-(piperidin-4-yl)phenyl)amino)-5-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyrazine-2-carboxamide [ka]

[0525] Step 1: 3-chloro-5-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyrazine-2-carbonitrile using 2-oxa-6-azaspiro[3.4]octan-6-yl)octane as the amine. LCMS C 11 H 11 ClNO theoretical value: 250 Measured value: m / z=251 [M+H] + .

[0473]

[0526] Step 2: tert-Butyl 4-(4-((3-cyano-6-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyrazin-2-yl)amino)phenyl)piperidine-1-carboxylate. LCMS C 27 H 34 N6O3 theoretical value: 490 Measured value: m / z = 491 [M+H] + .

[0474]

[0527] Step 3: tert-Butyl 4-(4-((3-carbamoyl-6-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyrazin-2-yl)amino)phenyl)piperidine-1-carboxylate. LCMS C 27 H 36 N6O4 theoretical value: 508 Measured value: m / z = 509 [M+H] + .

[0475]

[0528] Step 4: 3-((4-(piperidin-4-yl)phenyl)amino)-5-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyrazine-2-carboxamide. LCMS C 22 H 28 N6O2 theoretical value: 408 Measured value: m / z = 409 [M+H] + .

[0476] Example 12F: 3-((4-(piperidin-4-yl)phenyl)amino)-5-(1H Synthesis of (pyrazol-1-yl)pyrazine-2-carboxamide [ka]

[0530] Step 1: 3-chloro-5-(1H-pyrazol-1-yl)pyrazine-2-carbonitrile using pyrazole as the amine. LCMS C8H4ClN5 Calcd: 205 Found: m / z = 206 [M+H] + .

[0477]

[0531] Step 2: tert-Butyl 4-(4-((3-cyano-6-(1H-pyrazol-1-yl)pyrazin-2-yl)amino)phenyl)piperidine-1-carboxylate. LCMS C 24 H 27 N7O2 theoretical value: 445 Measured value: m / z = 446 [M+H] + .

[0478]

[0532] Step 3: tert-Butyl 4-(4-((3-carbamoyl-6-(1H-pyrazol-1-yl)pyrazin-2-yl)amino)phenyl)piperidine-1-carboxylate. LCMS C 24 H 29 N7O3 theoretical value: 463 Measured value: m / z = 464 [M+H] + .

[0479]

[0533] Step 4: 3-((4-(piperidin-4-yl)phenyl)amino)-5-(1H-pyrazol-1-yl)pyrazine-2-carboxamide. LCMS C 19 H 21 NO Theoretical value: 363 Measured value: m / z = 364 [M+H] + .

[0480] Example 12G: Synthesis of 3-((4-(piperidin-4-yl)phenyl)amino)-5-(3-(trifluoromethyl)-1H-pyrazol-1-yl)pyrazine-2-carboxamide [ka]

[0535] Step 1: 3-chloro-5-(3-(trifluoromethyl)-1H-pyrazol-1-yl)pyrazine-2-carbonitrile using 3-trifluoromethylpyrazole as the amine. LCMS C9H3ClF3N5 Calcd: 273 Found: m / z=274 [M+H] + .

[0481]

[0536] Step 2: tert-Butyl 4-(4-((3-cyano-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)pyrazin-2-yl)amino)phenyl)piperidine-1-carboxylate. LCMS C 25 H 26 F3N7O2 theoretical value: 513 Measured value: m / z = 514 [M+H] + .

[0482]

[0537] Step 3: tert-Butyl 4-(4-((3-carbamoyl-6-(3-(trifluoromethyl)-1H-pyrazol-1-yl)pyrazin-2-yl)amino)phenyl)piperidine-1-carboxylate. LCMS C 25 H 28 F3N7O3 theoretical value: 531 Measured value: m / z = 532 [M+H] + .

[0483]

[0538] Step 4: 3-((4-(piperidin-4-yl)phenyl)amino)-5-(3-(trifluoromethyl)-1H-pyrazol-1-yl)pyrazine-2-carboxamide. LCMS C 20 H 20 F3N7O Theoretical value: 431 Measured value: m / z = 432 [M+H] + .

[0484] Example 13: Synthesis of (R)-4-((3-carbamoyl-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)benzoic acid [ka] Step 1: Methyl (R)-4-((3-cyano-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)benzoate

[0541] (R)-3-chloro-5-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazine-2-carbonitrile, methyl 4-aminobenzoate (1 equivalent), Pd(OAc)2 (0.15 equivalents), BINAP (0.15 equivalents), and cesium carbonate (2 equivalents) were combined in a microwave tube, followed by the addition of dioxane (0.25 M). Nitrogen was bubbled thoroughly for 30 seconds and then the tube was capped. The mixture was stirred at 90 °C for 3 hours. The reaction was then cooled and filtered through Celite, rinsing with ethyl acetate / methanol. The crude material was purified by MPLC (0-10% MeOH in CH2Cl2) to give methyl (R)-4-((3-cyano-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)benzoate (74% yield). LCMS C 22 H 25 N7O3 theoretical value: 435.5, measured value: m / z = 436.6 [M+H] + .

[0485] Step 2: Methyl (R)-4-((3-carbamoyl-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)benzoate

[0543] Methyl (R)-4-((3-cyano-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)benzoate was dissolved in methanol / DMSO (10:1) and NaOH pellets were added. The reaction was stirred for 5 minutes, after which 35% peroxide solution (2 mL of solution per mmol of reactant) was added. The reaction mixture was stirred for 3 hours and then partitioned between ethyl acetate and water. The organic layer was separated and dried over magnesium sulfate. Chromatography (0-10% methanol in DCM) provided methyl (R)-4-((3-carbamoyl-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)benzoate in 48% yield. LCMS C 22 H 27N7O4 theoretical value: 453.5, measured value: m / z = 454.6 [M+H] + .

[0486] Step 3: (R)-4-((3-carbamoyl-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)benzoic acid

[0545] The starting material was dissolved in THF (0.1 M) and then 2N LiOH (aqueous, 25% by volume of THF) was added. The reaction was stirred at 80° C. for 4 hours. The reaction was then poured into ethyl acetate / 2N HCl in a separatory funnel. The organic layer was separated and the aqueous layer was further extracted with methylene chloride / methanol (10%). Both organic layers were dried over magnesium sulfate, filtered, and concentrated to provide (R)-4-((3-carbamoyl-6-(3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl)pyrazin-2-yl)amino)benzoic acid (88% yield) without further purification. LCMS C 21 H 25 N7O4 theoretical value: 439.5, measured value: m / z = 440.6 [M+H] + .

[0487] Example 14: General Procedure A [ka]

[0547] When used in General Procedure A, "Linker A" is -X 2 -X 3 -X 4 -X 5 - where X 2 , X 3 , X 4 , and X 5 Each of the is defined above for compounds of formula (A).

[0488]

[0548] Step 1: A mixture of 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (0.26 mmol), amino ester (0.26 mmol), ethylbis(propan-2-yl)amine (0.52 mmol), and DMF (1 mL) was stirred overnight at 90° C. The mixture was cooled and purified by HPLC (5-95% MeCN in HO containing 0.1% TFA) to give the tert-butyl ester intermediate.

[0489]

[0549] Step 2: tert-Butyl 4-{[2-(2,6-dioxopiperidine- A mixture of (3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}butanoate (0.10 mmol), CHCl (1 mL), and TFA (1 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to give the carboxylic acid product.

[0490] Example 14A: Synthesis of 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)propanoic acid [ka]

[0551] Step 1 product: tert-butyl 3-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]propanoate (1.8 g, 51.9%). LCMS; C 22 H 27 N3O7 theoretical value: 445, measured value: m / z = 468 [M+Na] + .

[0491]

[0552] Step 2 product: 3-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]propanoic acid (526.8 mg, 32%). LCMS; C 18 H 19N3O7 theoretical value: 389, measured value: m / z = 390 [M+H] + .

[0492] Example 14B: Synthesis of 3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoic acid [ka]

[0554] Step 1 product: tert-butyl 3-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxoisoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]propanoate (1.6 g, 41%). LCMS; C 26 H 35 N3O9 theoretical value: 533, measured value: m / z = 534 [M+H] + .

[0493]

[0555] Step 2 product: 3-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]propanoic acid (1.2 g, 73.62%). LCMS; C 22 H 27 N3O9 theoretical value: 477, measured value: m / z = 478 [M+H] + .

[0494] Example 14C: Synthesis of trans-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)cyclohexane-1-carboxylic acid [ka]

[0557] Product of Step 1: trans-tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)cyclohexane-1-carboxylate (43.40 mg, 47.0%).

[0495]

[0558] Product of Step 2: trans-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)cyclohexane-1-carboxylic acid (38 mg, 99%).

[0496] Example 14D: Synthesis of 3-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-3-oxopropoxy)propanoic acid [ka]

[0560] Step 1: A mixture of lenalidomide (270 mg, 1.04 mmol), 3-[3-(tert-butoxy)-3-oxopropoxy]propanoic acid (250 mg, 1.15 mmol), HATU (515 mg, 1.35 mmol), ethylbis(propan-2-yl)amine (0.73 mL, 4.17 mmol), and DMF (5 mL) was stirred at room temperature for 6 hours. EtOAc and HO were added. The organic layer was dried over MgSO, filtered, concentrated, and purified by MPLC (20-100% EtOAc in hexanes) to give tert-butyl 3-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-4-yl]carbamoyl}ethoxy)propanoate (307 mg, 64%). LCMS: C 23 H 29 N3O7 theoretical value: 459, measured value: m / z = 460 [M+H] + .

[0497]

[0561] Step 2: A mixture of tert-butyl 3-(2-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-4-yl]carbamoyl}ethoxy)propanoate (307 mg, 0.67 mmol), CHCl (5 mL), and TFA (1 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to give 3-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-3-oxopropoxy)propanoic acid (269 mg, 99%). LCMS: C 19 H 21 N3O7 theoretical value: 403, measured value: m / z = 404 [M+H] + .

[0498] Example 15: General Procedure B [ka] Step 1: 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione

[0564] A mixture of 5-fluoro-1,3-dihydro-2-benzofuran-1,3-dione (5.0 g, 30.10 mmol), 3-aminopiperidine-2,6-dione hydrochloride (6.9 g, 42.14 mmol), and NaOAc (4.2 g, 51.17 mmol) in HOAc (50 mL) was stirred at 120 °C for 5 hours and then concentrated in vacuo. The residue was washed with water, and the solid was collected by filtration. The crude product was washed twice with water and twice with ethyl acetate and dried in an oven to give 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (7.7 g, 92%) as a light brown solid. 1 H NMR(300MHz,DMSO-d6)δ11.16(s,1H),8.03-8.00(m,1H),7.87-7.85(m,1H),7.75-7.7 0(m,1H),5.19-5.15(m,1H),2.94-2.86(m,1H),2.63-2.48(m,2H),2.12-2.06(m,1H).F NMR (300MHz, DMSO-d6)δ -102.078.

[0499] Step 2: Amine substitution of aryl fluorides

[0566] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3-dione (1.0 g, 3.62 mmol) in N-methylpyrrolidone (10 mL) was added amine (3.60 mmol) and DIEA (1.4 g, 10.83 mmol). The resulting solution was stirred at 80° C. for 16 hours. The reaction mixture was cooled to room temperature and purified by reverse-phase flash chromatography to give the corresponding final product.

[0500] Step 3: Oxidation of the alcohol to an aldehyde

[0568] To a mixture of the alcohol (1.06 mmol) in CHCl (10 mL) was added Dess-Martin periodinane (2.12 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was purified by column chromatography to give the desired aldehyde.

[0501] Example 15A: Synthesis of 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetaldehyde [ka] Step 2: General procedure B was followed using 2-(piperidin-4-yl)ethan-1-ol to afford 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-hydroxyethyl)piperidin-1-yl)isoindoline-1,3-dione (822.8 mg, 59%) as a yellow solid. 1H NMR(300MHz,DMSO-d6)δ11.09(s,1H),7.65(d,J=8.4Hz,1H),7.30(d,J=2.4Hz,1H ),7.23(dd,J=8.4,2.4Hz,1H),5.07(dd,J=12.6,5.4Hz,1H),4.40(t,J=5.1Hz,1H ),4.04(d,J=13.2Hz,2H),3.64-3.40(m,2H),3.09-2.79(m,3H),2.70-2.51(m,2H ),2.07-1.94(m,1H),1.77-1.66(m,3H),1.41-1.34(m,2H),1.24-1.12(m,2H).(C 20 H 23 MS(ESI) calculated for N3O5)[M+H]+, 386.2; found 386.1.

[0502]

[0571] Step 3: 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetaldehyde LCMS C 20 H 21 N3O5 theoretical value: 383, measured value: m / z = 384 [M+H] + .

[0503] Example 15B: Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbaldehyde [ka] Step 2: General procedure B was followed using azetidin-3-ylmethanol hydrochloride to afford 2-(2,6-dioxopiperidin-3-yl)-5-(3-(hydroxymethyl)azetidin-1-yl)isoindoline-1,3-dione (1.85 g, 68%) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),7.63(d,J=8.4Hz,1H),6.76(d,J=2.0Hz,1H),6.62(dd,J=8.4,2.0Hz,1H),5.06(dd,J=12.4,5.2Hz,1H),4.86(t ,J=5.2Hz,1H),4.05(t,J=8.4Hz,2H),3.77(dd,J=8.4,5.2Hz,2H),3.60(t ,J=5.2Hz,2H),3.00-2.81(m,2H),2.65-2.53(m,2H),2.06-1.96(m,1H).(C 17 H 17 N3O5)[M+H] + MS(ESI) calculated for 344.1; found 344.4.

[0504]

[0574] Step 3: 1-(2-(2,6-dioxopiperidin-3-yl)-1,3 (Dioxoisoindolin-5-yl)azetidine-3-carbaldehyde LCMS C 17 H 15 N3O5 theoretical value: 341, measured value: m / z = 343 [M+H] + .

[0505] Example 15C: Synthesis of 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)acetaldehyde [ka]

[0576] Step 2: Following general procedure B using 2-(azetidin-3-yl)ethan-1-ol hydrochloride gave 2-(2,6-dioxopiperidin-3-yl)-5-(3-(2-hydroxyethyl)azetidin-1-yl)isoindoline-1,3-dione (584.5 mg, 30%) as a yellow solid. 1H NMR(300MHz,DMSO-d6)δ11.09(s,1H),7.63(d,J=8.4Hz,1H),6.75(d,J=2.1Hz,1 H),6.62(dd,J=8.4,2.1Hz,1H),5.06(dd,J=12.6,5.4Hz,1H),4.51(t,J=5.1Hz,1 H),4.14(t,J=8.1Hz,2H),3.71-3.67(m,2H),3.47-3.40(m,2H),2.99-2.75(m,2H) ),2.61-2.58(m,1H),2.52-2.46(m,1H),2.10-1.95(m,1H),1.82-1.76(m,2H).(C 18 H 19 N3O5)[M+H] + MS(ESI) calculated for 358.1; found 358.4.

[0506]

[0577] Step 3: 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidin-3-yl)acetaldehyde LCMS C 18 H 17 N3O5 theoretical value: 355, measured value: m / z = 356 [M+H] + .

[0507] Example 15D: Synthesis of (3R)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-3-carbaldehyde [ka]

[0579] Step 2: General procedure B was followed using (R)-piperidin-3-ylmethanol hydrochloride to afford 2-(2,6-dioxopiperidin-3-yl)-5-((R)-3-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione (916.3 mg, 45%) as a yellow solid. 1H NMR(400MHz,DMSO-d6 / D2O)δ7.62(d,J=8.4Hz,1H),7.22(d,J=2.4Hz,1H),7.16(dd,J=8.4,2.4Hz,1H),4.99(dd,J=12 .8,5.2Hz,1H),3.98-3.76(m,2H),3.42-3.22(m,2H),3.08-2.90(m,1H),2.89-2.71(m,2H),2.61-2.43(m,2H),2.02-1 .99(m,1H),1.73-1.69(m,3H),1.49-1.40(m,1H),1.26-1.18(m,1H).(C 19 H 21 N3O5)[M+H] + MS(ESI) calculated for 372.1; found 372.4.

[0508]

[0580] Step 3: (3R)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-3-carbaldehyde LCMS C 19 H 19 N3O5 theoretical value: 369, measured value: m / z = 370 [M+H] + .

[0509] Example 15E: Synthesis of (3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-3-carbaldehyde [ka]

[0582] Step 2: General procedure B was followed using (S)-piperidin-3-ylmethanol hydrochloride to afford 2-(2,6-dioxopiperidin-3-yl)-5-((S)-3-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione (493.1 mg, 73%) as a yellow solid. 1H NMR(300MHz,DMSO-d6 / D2O)δ7.65(d,J=8.4Hz,1H),7.26(d,J=2.1Hz,1H),7.19(dd,J=8.4,2.1Hz,1H),5.04(dd,J=12.9,5.4Hz,1H),4.00-3.90 (m,2H),3.38-3.32(m,2H),3.13-2.71(m,3H),2.67-2.44(m,2H),2.03- 1.98(m,1H),1.76-1.67(m,3H),1.57-1.38(m,1H),1.34-1.10(m,1H).(C 19 H 21 N3O5)[M+H] + MS(ESI) calculated for 372.1; found 372.1.

[0510]

[0583] Step 3: (3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-3-carbaldehyde LCMS C 19 H 19 N3O5 theoretical value: 369, measured value: m / z = 370 [M+H] + .

[0511] Example 15F: Synthesis of (3R)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine-3-carbaldehyde [ka]

[0585] Step 2: General procedure B was followed using (R)-pyrrolidin-3-ylmethanol to afford 2-(2,6-dioxopiperidin-3-yl)-5-((R)-3-(hydroxymethyl)pyrrolidin-1-yl)isoindoline-1,3-dione (480.6 mg, 74%) as a yellow solid. 1H NMR(300MHz,DMSO-d6)δ11.08(s,1H),7.64(d,J=8.4Hz,1H),6.89(d,J=2.1Hz,1H),6.80(dd,J=8.4,2.1Hz,1H),5.06(dd,J=12.9,5.4Hz (C) 18 H 19 N3O5)[M+H] + MS(ESI) calculated for 358.1; found 358.1.

[0512]

[0586] Step 3: (3R)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine-3-carbaldehyde LCMS C 18 H 17 N3O5 theoretical value: 355, measured value: m / z = 356 [M+H] + .

[0513] Example 15G: Synthesis of (3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine-3-carbaldehyde [ka]

[0588] Step 2: General procedure B was followed using (S)-pyrrolidin-3-ylmethanol to afford 2-(2,6-dioxopiperidin-3-yl)-5-((S)-3-(hydroxymethyl)pyrrolidin-1-yl)isoindoline-1,3-dione (643.1 mg, 33%) as a yellow solid. 1H NMR(300MHz,DMSO-d6)δ11.08(s,1H),7.64(d,J=8.4Hz,1H),6.89(d,J=2.1Hz,1H),6.80(dd,J=8.4,2.1Hz,1H),5.06(dd,J=12.9,5.4Hz,1H) ,4.78(t,J=5.4Hz,1H),3.59-3.41(m,5H),3.22-3.17(m,1H),2.95-2. 83(m,1H),2.67-2.44(m,3H),2.12-1.88(m,2H),1.87-1.76(m,1H).(C 18 H 19 N3O5)[M+H] + MS(ESI) calculated for 358.1; found 358.1.

[0514]

[0589] Step 3: (3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine-3-carbaldehyde LCMS C 18 H 17 N3O5 theoretical value: 355, measured value: m / z = 356 [M+H] + .

[0515] Example 15H: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-((1R,5S,6r)-6-(hydroxymethyl)-3-aza-bicyclo[3.1.0]hexan-3-yl)isoindoline-1,3-dione [ka]

[0591] Step 2: General procedure B was followed using ((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-yl)methanol to afford 2-(2,6-dioxopiperidin-3-yl)-5-((1R,5S,6r)-6-(hydroxymethyl)-3-aza-bicyclo[3.1.0]hexan-3-yl)isoindoline-1,3-dione (315.8 mg, 21%) as a yellow solid. 1H NMR(300MHz,DMSO-d6)δ11.08(s,1H),7.63(d,J=8.4Hz,1H),6.92(d,J=2.1Hz,1H),6.82(dd,J=8.4,2.1Hz,1H),5.06(dd,J=12.6,5.4Hz,1H),4.59 (t,J=5.4Hz,1H),3.64-3.60(m,2H),3.50-3.35(m,4H),3.00-2.76(m,1H) ,2.58-2.44(m,2H),2.07-1.91(m,1H),1.69(s,2H),0.86-0.79(m,1H).(C 19 H 19 N3O5)[M+H] + MS(ESI) calculated for 370.1; found 370.1.

[0516]

[0592] Step 3: (1R,5S,6r)-3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-azabicyclo[3.1.0]hexane-6-carbaldehyde LCMS C 19 H 17 N3O5 theoretical value: 367, measured value: m / z = 368 [M+H] + .

[0517] Example 16: General Procedure C [ka]

[0594] When used in General Procedure B, "Linker B" is -(CH2-CH2-O) x -, where x is an integer from 1 to 3.

[0518]

[0595] Step 1: 3-(4-bromo-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (2.52 mmol), (PPh A mixture of 2PdCl2 (0.15 mmol), CuI (0.25 mmol), and alkyne ester (5.04 mmol) was added to the vial. The vial was evacuated and backfilled with N2 five times. DMF and triethylamine (30.3 mmol) were added, and the mixture was stirred at 90 °C overnight. The mixture was filtered through Celite and washed with MeOH and EtOAc. EtOAc and saturated aqueous NaCl were added. The organic layer was dried over MgSO4, filtered, concentrated, and purified by reverse-phase MPLC (5-100% MeCN in HO on a C18 column) to give the product.

[0519]

[0596] Step 2: A mixture of disubstituted alkyne (0.81 mmol), Pd / C 10 wt% (0.08 mmol), and EtOH was mixed in a flask. The flask was evacuated and backfilled with H2 five times and stirred at room temperature for 2 h. The mixture was filtered through Celite, washed with MeOH and EtOAc, concentrated, and carried to the next step.

[0520]

[0597] Step 3: A mixture of tert-butyl ester (0.81 mmol), CH2Cl2 (2 mL), and TFA (2 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to give the carboxylic acid product.

[0521] Example 16A: Synthesis of 3-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propoxy)propanoic acid [ka]

[0599] Step 1 product: tert-butyl 3-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop-2-yn-1-yl)oxy)propanoate (347 mg, 32.3%). LCMS: C 23 H 26 N2O6 theoretical value: 426, measured value: m / z = 427 [M+H] + .

[0522]

[0600] Step 2 product: tert-butyl 3-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propoxy)propanoate (350 mg, 99%). LCMS: C 23 H 30 N2O6 theoretical value: 430, measured value: m / z = 431 [M+H] + .

[0523]

[0601] Step 3 product: 3-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propoxy)propanoic acid (304 mg, 99%). LCMS: C 19 H 22 N2O6 theoretical value: 374, measured value: m / z = 375 [M+H] + .

[0524] Example 17: Synthesis of (1s,3s)-3-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propoxy)cyclobutane-1-carboxylic acid [ka] Step 1: tert-Butyl 3-oxocyclobutane-1-carboxylate

[0604] To a solution of 3-oxocyclobutane-1-carboxylic acid (5.0 g, 43.82 mmol) and DMAP (2.7 g, 21.91 mmol) in t-BuOH (20 mL) and THF (20 mL) was added a solution of BocO (14.3 g, 65.73 mmol) in THF (10 mL) dropwise at 0 °C under a nitrogen atmosphere. The mixture was stirred at room temperature for 16 h. The reaction was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by flash column chromatography using 0–15% ethyl acetate in petroleum ether to give tert-butyl 3-oxocyclobutane-1-carboxylate (6.2 g, 83%) as a colorless oil. (C9H 14O3) [M+1] + MS(ESI) calculated for 171.1; found 171.2. 1 H NMR (300 MHz, chloroform-d) δ 3.39-2.98 (m, 5H), 1.44 (s, 9H).

[0525] Step 2: tert-Butyl (1s,3s)-3-hydroxycyclobutane-1-carboxylate

[0606] To a solution of tert-butyl 3-oxocyclobutane-1-carboxylate (5.1 g, 29.96 mmol) in THF (50 mL) and MeOH (5 mL) was added NaBH (566.8 mg, 14.98 mmol) in portions at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 30 min. The reaction was then cooled to room temperature by the addition of ice water. The mixture was quenched with ethyl acetate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated in vacuo to give tert-butyl (1s,3s)-3-hydroxycyclobutane-1-carboxylate (4.8 g, 93%) as a pale yellow oil, which was used in the next step without further purification. (C9H 16 O3) [M+1] + MS(ESI) calculated for 173.1; found 173.0. 1 H NMR (300 MHz, chloroform-d) δ 4.20-4.07 (m, 1H), 2.61-2.43 (m, 3H), 2.30 (s, 1H), 2.17-2.20 (m, 2H), 1.43 (s, 9H).

[0526] Step 3: tert-Butyl (1s,3s)-3-(prop-2-yn-1-yloxy)cyclobutane-1-carboxylate

[0608] To a solution of tert-butyl (1s,3s)-3-hydroxycyclobutane-1-carboxylate (5.0 g, 29.03 mmol) and 3-bromoprop-1-yne (3.8 g, 31.94 mmol) in THF was added t-BuOK (32 mL, 1 M in THF, 32.0 mmol) dropwise at 0 °C under a nitrogen atmosphere. The mixture was stirred at room temperature for 16 h. The reaction was then quenched by the addition of ice water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by flash column chromatography using 0–20% ethyl acetate in petroleum ether to give tert-butyl (1s,3s)-3-(prop-2-yn-1-yloxy)cyclobutane-1-carboxylate (3.2 g, 52%) as a pale yellow oil. (C 12 H 18 O3) [M+1] + MS(ESI) calculated for 211.1; found 211.3. 1 H NMR (300 MHz, chloroform-d) δ 4.17-3.99 (m, 3H), 2.63-2.43 (m, 3H), 2.29-2.11 (m, 2H), 2.04 (s, 1H), 1.44 (s, 9H).

[0527] Step 4: tert-Butyl (1s,3s)-3-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop-2-yn-1-yl)oxy)cyclobutane-1-carboxylate

[0610] A mixture of 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3.3 g, 10.21 mmol), tert-butyl (1s,3s)-3-(prop-2-yn-1-yloxy)cyclobutane-1-carboxylate (3.2 g, 15.32 mmol), Pd(PPh)Cl (1.1 g, 1.53 mmol), and CuI (486.2 mg, 2.55 mmol) in triethylamine (30 mL) and DMF (30 mL) was stirred at 80 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, the reaction was diluted with saturated aqueous NHCl and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by flash column chromatography using 0-10% ethyl acetate in methanol to give tert-butyl (1s,3s)-3-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop-2-yn-1-yl)oxy)cyclobutane-1-carboxylate (1.5 g, 27%) as a pale yellow solid. (C 25 H 28 N2O6)[M+1] + MS(ESI) calculated for 453.2; found 453.3.

[0528] Step 5: tert-Butyl (1s,3s)-3-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propoxy)cyclobutane-1-carboxylate

[0612] To a solution of tert-butyl (1s,3s)-3-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop-2-yn-1-yl)oxy)cyclobutane-1-carboxylate (1.5 g, 2.75 mmol) in MeOH (20 mL) was added Pd / C (10%, 200 mg) under a nitrogen atmosphere. The mixture was stirred under a hydrogen atmosphere (2 atm) at room temperature for 16 hours. The solid was filtered through a Celite pad, and the filtrate was concentrated under vacuum. The residue was purified by reverse-phase flash column chromatography using 10-70% acetonitrile in water to give tert-butyl (1s,3s)-3-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propoxy)cyclobutane-1-carboxylate (650 mg, 43%) as a pale yellow solid. (C 25 H 32 N2O6)[M+1] + MS(ESI) calculated for 457.2; found 457.3.

[0529] Step 6: (1s,3s)-3-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propoxy)cyclobutane-1-carboxylic acid

[0614] A mixture of tert-butyl (1s,3s)-3-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propoxy)cyclobutane-1-carboxylate (1.2 g, 2.63 mmol) in TFA (4 mL) and DCM (12 mL) was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was purified by reverse-phase flash column chromatography to give (1s,3s)-3-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propoxy)cyclobutane-1-carboxylic acid (968.7 mg, 92%). (C 21 H 24 N2O6)[M+1] + MS(ESI) calculated for 401.2; found 400.8. 1H NMR(300MHz,DMSO-d6)δ12.12(s,1H),10.97(s,1H),7.59-7.53(m,1H),7 .48-7.41(m,2H),5.15-5.09(m,1H),4.45(d,J=17.1Hz,1H),4.29(d,J=17 .1Hz,1H),3.89-3.69(m,1H),3.27(t,J=6.3Hz,2H),2.97-2.85(m,1H),2. 77-2.51(m,4H),2.46-2.28(m,3H),2.14-1.73(m,3H),1.86-1.73(m,2H).

[0530] Example 18: Synthesis of 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione [ka] Step 1: Methyl 3-bromo-2-(bromomethyl)benzoate [ka]

[0617] To a solution of methyl 3-bromo-2-methyl-benzoate (50 g, 218.27 mmol, 1 equiv.), NBS (46.62 g, 261.93 mmol, 1.2 equiv.) in CHCl3 (400 mL) was added AIBN (3.58 g, 21.83 mmol, 0.1 equiv.). The mixture was stirred at 70 °C for 12 h. The reaction mixture was concentrated in vacuo, diluted with DCM (400 mL), washed with HO (100 mL) and brine (100 mL), extracted with DCM (100 mL), and washed again with brine (50 mL). The organic phases were combined and washed with Na The mixture was dried over SO and concentrated in vacuo, and the residue was purified by flash silica gel chromatography (petroleum ether / ethyl acetate=100 / 1) to give 3-bromo-2-(bromomethyl)benzoate (63 g, 204.57 mmol, 93.72% yield) as a pale yellow solid.

[0531] Step 2: 3-(4-Bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione [ka]

[0619] To a solution of methyl 3-bromo-2-(bromomethyl)benzoate (88.2 g, 286.39 mmol, 1 equiv.) in ACN (600 mL) was added DIEA (49.23 g, 380.91 mmol, 66.35 mL, 1.33 equiv.) and 3-aminopiperidine-2,6-dione hydrochloride (51.01 g, 309.94 mmol, 1.08 equiv.). The mixture was stirred at 80° C. for 16 hours. The reaction mixture was filtered. The filter cake was triturated with the mixture solution (100 mL:200 mL of EtOAc:HO). ) to give 3-(4-bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (56.5 g, 174.85 mmol, 61.05% yield) as a purple powder.

[0532] Example 19: Synthesis of 2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propyl)piperazin-1-yl)acetic acid [ka] Step 1: tert-Butyl 2-(4-(prop-2-ynyl)piperazin-1-yl)acetate

[0622] To a solution of tert-butyl 2-(piperazin-1-yl)acetate (1.5 g, 7.49 mmol) in acetonitrile (50 mL) was added 3-bromoprop-1-yne CsCO (892.5 mg, 7.50 mmol) and CsCO (2.4 g, 7.50 mmol) were added. The resulting solution was stirred at room temperature for 4 hours. The solids were filtered, and the filtrate was evaporated under vacuum. The residue was purified by phase flash column chromatography using 0-30% ethyl acetate in petroleum ether to give tert-butyl 2-(4-(prop-2-ynyl)piperazin-1-yl)acetate (1.1 g, 62%) as a yellow oil. (C 13 H22 N2O2)[M+H] + MS(ESI) calculated for 239.2; found 239.1.

[0533] Step 2: tert-butyl 2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop-2-ynyl)piperazin-1-yl)acetate

[0624] To a degassed solution of 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.5 g, 4.64 mmol) in N,N-dimethylformamide (30 mL) was added tert-butyl 2-(4-(prop-2-ynyl)piperazin-1-yl)acetate (1.5 g, 6.29 mmol), Pd(PPh)Cl (489.0 mg, 0.70 mmol), DIEA (20 mL), and CuI (221.7 mg, 1.16 mmol). The resulting solution was stirred at 75 °C under nitrogen for 16 h. The reaction was quenched by the addition of water and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated in vacuo. The residue was purified by flash column chromatography using 0-10% methanol in dichloromethane to give tert-butyl 2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop-2-ynyl)piperazin-1-yl)acetate (1.5 g, 68%) as a yellow solid. (C 26 H 32 N4O5)[M+H] + MS(ESI) calculated for 481.2; found 481.1.

[0534] Step 3: tert-butyl 2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propyl)piperazin-1-yl)acetate

[0626] To a solution of tert-butyl 2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop-2-ynyl)piperazin-1-yl)acetate (2.2 g, 4.58 mmol) in methanol (50 mL) was added Pd / C (dry, 0.44 g). The resulting solution was stirred under hydrogen (2 atm) at room temperature for 16 hours. The solid was filtered. The filtrate was evaporated in vacuo to give tert-butyl 2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propyl)piperazin-1-yl)acetate (1.4 g, crude) as a yellow oil, which was used in the next step without further purification. (C 26 H 36 N4O5)[M+H] + MS(ESI) calculated for 485.3; found 485.2.

[0535] Step 4: 2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propyl)piperazin-1-yl)acetic acid TFA salt

[0628] To a solution of tert-butyl 2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propyl)piperazin-1-yl)acetate (1.4 g, 2.89 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (20 mL). The resulting solution was stirred at room temperature for 16 hours and then concentrated in vacuo. The residue was purified by HPLC (MeCN / H2O with TFA) to give 2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propyl)piperazin-1-yl)acetic acid TFA salt (434.3 mg, 35%) as a yellow solid. (C 22 H 28 N4O5)[M+H] + MS (ESI) Calculated value, 429.2; Measured value, 429.0. 1H NMR(300MHz,DMSO-d6)δ11.08(s,1H),7.60-7.65(m,1H),7.52-7.47(m,2H),5.20-5.13(m,1H),4.52-4.46(m,1 H),4.35-4.29(m,1H),3.51(s,3H),3.47-2.84(m,9H),2.72-2.50(m,4H),2.49-2.31(m,1H),2.05-1.97(m,3H).

[0536] Example 20: Synthesis of 2-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethyl)piperazin-1-yl)acetic acid [ka] Step 1: Benzyl 4-(2-(tert-butoxy)-2-oxoethyl)piperazine-1-carboxylate

[0631] To a solution of benzyl piperazine-1-carboxylate (10.0 g, 45.4 mmol) and K2CO3 (12.6 g, 90.8 mmol) in acetonitrile (150 mL) was added tert-butyl 2-chloroacetate (7.5 g, 49.9 mmol). The resulting solution was stirred at 40 °C under a nitrogen atmosphere for 16 h. The solids were filtered, and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography using 0 to 50% ethyl acetate in petroleum ether to give benzyl 4-(2-(tert-butoxy)-2-oxoethyl)piperazine-1-carboxylate (9.6 g, 63%) as a pale yellow oil. (C 18 H 26 N2O4)[M+H] + MS(ESI) calculated for 335.2; found 335.3.

[0537] Step 2: tert-Butyl 2-(piperazin-1-yl)acetate

[0633] Benzyl 4-(2-(tert-butoxy)-) in methanol (100 mL) To a solution of 2-oxoethyl)piperazine-1-carboxylate (9.6 g, 28.7 mmol) was added Pd / C (10%, 2.0 g) under a nitrogen atmosphere. The mixture was stirred at room temperature under a hydrogen atmosphere (2 atm) for 16 hours. The solid was filtered, and the filtrate was concentrated in vacuo to give tert-butyl 2-(piperazin-1-yl)acetate (6.2 g, crude) as a pale yellow oil, which was used in the next step without further purification. (C 10 H 20 N2O2)[M+H] + MS(ESI) calculated for 201.2; found 201.0.

[0538] Step 3: 3-(4-allyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0635] A degassed mixture of 3-(4-bromo-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (10.0 g, 30.9 mmol), allyltributylstannane (15.4 g, 46.4 mmol), and Pd(PPh3)4 (3.6 g, 3.1 mmol) in DMF (80 mL) was stirred at 100 °C under a nitrogen atmosphere for 16 h. Upon completion of the reaction by LCMS, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 0–10% methanol in dichloromethane to give 3-(4-allyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (7.0 g, 79%) as a white solid. (C 16 H 16 N2O3)[M+H] +MS(ESI) calculated value for, 285.1; measured value, 285.2. 1H NMR(400MHz,DMSO-d6)δ10.99(s,1H),7.62-7.60(m,1H),7.52-7.27(m,2H),6.02-5.92(m,1H),5.16-5.09(m,3H),4.45(d,J=17. 2Hz,1H), 4.30(d,J=17.2Hz,1H),3.46-3.44(m,2H),2.97-2.86(m,1H),2.70-2.57(m,1H),2.04-1.99(m,1H),1.68-1.55(m,1H).

[0539] Step 4: 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetaldehyde

[0637] A mixture of 3-(4-allyl-1-oxoisoindolin-2-yl)piperidine-2,6-dione (7.0 g, 24.6 mmol), OsO (625 mg, 2.5 mmol), and NaIO (10.5 g, 49.2 mmol) in MeCN (60 mL) and HO (20 mL) was stirred at 0 °C for 6 h. Upon completion of the reaction, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetaldehyde (4.0 g, crude) as a brown solid, which was used in the next step without further purification. (C 15 H 14 N2O4)[M+H] + MS(ESI) calculated for 287.1; found 287.2.

[0540] Step 5: tert-butyl 2-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethyl)piperazin-1-yl)acetate

[0639] A mixture of 2-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]acetaldehyde (4.0 g, 13.9 mmol), tert-butyl 2-(piperazin-1-yl)acetate (3.4 g, 16.8 mmol), AcOH (1 mL), and NaBH(OAc) (5.9 g, 27.9 mmol) in dichloromethane (50 mL) was stirred at room temperature for 16 hours. The resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. A 10-50% solution of acetonitrile in water was added. The crude residue was purified by reverse-phase flash column chromatography using a cyclohexane-1,2-dimethyl-2,3-dimethyl-1,4-dimethyl-2,5-dimethyl-1,6-dimethyl-2,6-dimethyl-1,6-dimethyl-2,5 ... 25 H 34 N4O5)[M+H] + MS(ESI) calculated for 471.2; found 471.0.

[0541] Step 6: 2-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethyl)piperazin-1-yl)acetic acid TFA salt

[0641] To a solution of tert-butyl 2-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethyl)piperazin-1-yl)acetate (2.5 g, 5.3 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (20 mL). The resulting mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. The residue was purified by reverse-phase flash column chromatography using 5-30% acetonitrile in water to give 2-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethyl)piperazin-1-yl)acetic acid (1.7214 g, 78%) as a light brown solid. (C 21 H 26 N4O5)[M+H]+ MS(ESI) calculated for 415.2; found 415.4. 1 H NMR(300MHz,DMSO-d6)δ11.08(s,1H),7.66-7.62(m,1H),7.54-7.47(m,2H),5.14-5.08(m,1H),4.54-4.48(m,1H),4.40-4 .31(m,1H),3.76(s,2H),3.60-3.10(m,10H),3.10-2.78(m,3H),2.68-2.54(m,1H),2.40-2.31(m,1H),2.10-1.94(m,1H).

[0542] Example 21: Synthesis of 2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)piperazin-1-yl)acetic acid [ka] Step 1: tert-Butyl 2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1-yl)piperazin-1-yl)acetate

[0644] To a degassed solution of 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1.3 g, 3.86 mmol) in N,N-dimethylformamide (18 mL) was added tert-butyl 2-(4-(prop-2-ynyl)piperazin-1-yl)acetate (1.4 g, 5.57 mmol), Pd(PPh)Cl (423.3 mg, 0.60 mmol), DIEA (12 mL), and CuI (251.1 mg, 1.32 mmol). The resulting solution was heated under nitrogen at 75 °C for 4 hours. The mixture was stirred for 1 hour. The reaction was quenched by the addition of water and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated in vacuo. The residue was purified by flash column chromatography using 0-10% methanol in dichloromethane to give tert-butyl 2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1-yl)piperazin-1-yl)acetate (2.5 g, 70%) as a yellow solid. (C 26 H 30 N4O6)[M+H] + MS(ESI) calculated for 495.2; found 495.1.

[0543] Step 2: tert-butyl 2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)piperazin-1-yl)acetate

[0646] To a solution of tert-butyl 2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-ynyl)piperazin-1-yl)acetate (2.1 g, 4.25 mmol) in methanol (50 mL) was added Pd / C (dry, 0.42 g). The resulting solution was stirred under hydrogen (2 atm) at room temperature for 16 hours. The solid was filtered and the filtrate was evaporated in vacuo to give tert-butyl 2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)piperazin-1-yl)acetate (1.6 g, crude) as a yellow solid, which was used in the next step without further purification. (C 26 H 34 N4O6)[M+H] + MS(ESI) calculated for 499.2; found 499.0.

[0544] Step 3: 2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)piperazin-1-yl)acetic acid TFA salt

[0648] To a solution of tert-butyl 2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)piperazin-1-yl)acetate (2.1 g, 4.21 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (20 mL). The resulting solution was stirred at room temperature for 4 hours and then concentrated in vacuo. The residue was purified by pre-HPLC using the following conditions: [Column: XSelect CSH Prep C18 OBD column, 5 μm, 19*150 mm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 5% B to 20% B in 7 min; 254 / 220 nm] to give 2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)piperazin-1-yl)acetic acid TFA salt (398.0 mg, 21%) as a yellow solid. (C 22 H 26 N4O6)[M+H] + MS(ESI) calculated for 443.2; found 442.9. 1 H NMR(300MHz,DMSO-d6)δ11.15(s,1H),7.95-7.73(m,3H),5.17-5.11(m,1H),3.74-3.29(m,3H ),3.25-2.73(m,11H),2.64(s,1H),2.60-2.52(m,1H),2.46-2.45(m,1H),2.11-1.92(m,3H).

[0545] Example 22: General Procedure D [ka]

[0650] Step 1: To a solution of fluoro-benzofuran-1,3-dione (27.16 mmol) in HOAc (50 mL) was added sodium acetate (46.17 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (38.02 mmol). The reaction mixture was stirred at 120° C. for 5 hours. The mixture was cooled to room temperature and diluted with water. The solid was collected by filtration and dried to give the fluoroimide intermediate.

[0546]

[0651] Step 2: To a solution of fluoroimide (0.68 mmol) in DMF (30 mL) was added tert-butyl 4-(piperazin-1-yl)butanoate (0.68 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.4 mmol). The reaction mixture was stirred at 80° C. for 4 hours. The resulting mixture was cooled to room temperature and diluted with water. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine and water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the tert-butyl ester intermediate (3.3 g, crude), which was used in the next step without further purification.

[0547]

[0652] Step 3: To a solution of the tert-butyl ester intermediate (6.57 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (10 mL). The reaction mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo. The residue was purified by reverse-phase flash column chromatography (20-80% acetonitrile in water) to give the acid product (38% over two steps).

[0548] Example 22A: Synthesis of 4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)butanoic acid [ka]

[0654] Step 1 product: 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (3.0 g, 50%). LCMS: C13 H9FN2O4 theoretical value: 276, measured value: m / z = 277 [M+H] + .

[0549]

[0655] Step 2 product: tert-butyl 4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)butanoate (4.4 g, 84%). LCMS: C 25 H 32 N4O6 theoretical value: 484, measured value: m / z = 485 [M+H] + .

[0550]

[0656] Step 3 product: 4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)butanoic acid TFA salt (3.35 g, 56%). LCMS: C 21 H 24 N4O6 theoretical value: 428, measured value: m / z = 429 [M+H] + .

[0551] Example 23: General Procedure E [ka]

[0658] Step 1: 5-Bromo-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (347 mg, 1.03 mmol), (PPh3)3PdCl2 (43.4 mg, 0.06 mmol), and CuI (19.6 mg, 0.10 mmol) were added to a vial. The vial was evacuated and backfilled with N2 five times. DMF (0.00 g, 1.03 mmol), tert-butyl 3-(prop-2-yn-1-yloxy)propanoate (190 mg, 1.03 mmol), and triethylamine (1.72 mL, 12.4 mmol) were added, and the mixture was stirred at 90 °C overnight. The mixture was filtered through SiO, washed with EtOAc / MeOH, concentrated, and purified by HPLC (5-95% MeCN in HO with 0.1% TFA) to give tert-butyl 3-({3-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]prop-2-yn-1-yl}oxy)propanoate (173 mg, 38.2%).

[0552]

[0659] Step 2: A mixture of tert-butyl 3-({3-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]prop-2-yn-1-yl}oxy)propanoate (173 mg, 0.39 mmol), Pd / C 10 wt% (4.0 mg, 0.04 mmol), and EtOH (5 mL) was mixed in a flask. The flask was evacuated and backfilled with H 5 times and stirred at room temperature for 2 h. The mixture was filtered through Celite, washed with MeOH and EtOAc, concentrated, and carried on to the next step.

[0553]

[0660] Step 3: tert-Butyl 3-{3-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl]propoxy}propanoate A mixture of 3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)propoxy}propanoic acid (151 mg, 99.3%) was stirred at room temperature for 2 h.

[0554] Example No. 24: General Procedure F [ka]

[0662] Step 1: 3-(4-Bromo-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (1.79 mmol), (PPh3)2PdCl2 (0.11 mmol), and CuI (0.15 mmol) were added to a vial. The vial was evacuated and backfilled with N2 five times. DMF (5 mL), alkyne (4.37 mmol), and triethylamine (18.05 mmol) were added, and the mixture was stirred at 90 °C overnight. The mixture was filtered through Celite and purified by HPLC (5-95% MeCN in HO containing 0.1% TFA) to give the aryl alkyne (58%).

[0555]

[0663] Step 2: A mixture of aryl alkyne (1.04 mmol), Pd / C 10 wt% (0.12 mmol), and EtOH (0.15 mL) was mixed in a flask. The flask was evacuated and backfilled with H2 five times and stirred at room temperature for 16 h. The mixture was filtered through Celite, washed with MeOH and EtOAc, and concentrated to give the alkyl alcohol (74%).

[0556]

[0664] Step 3: Dess-Martin periodinane (1.54 mmol) was added to a mixture of alkyl alcohol (0.77 mmol) and CHCl (10 mL). The mixture was stirred at room temperature for 1 h. CHCl and aqueous NaSO were added. The organic layer was dried over MgSO, filtered, concentrated, and purified by MPLC (20-100% EtOAc in hexanes) to give the aldehyde.

[0557] Example 24A: Synthesis of 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propanal [ka]

[0666] Step 1 product: 3-(4-(3-hydroxyprop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (127.6 mg, 23.1%). LCMS: C 16 H 14 N2O4 theoretical value: 298, measured value: m / z = 299 [M+H] + .

[0558]

[0667] Step 2 product: 3-(4-(3-hydroxypropyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (129 mg, 99%). LCMS; C 16 H 18 N2O4 theoretical value: 302, measured value: m / z = 303 [M+H] + .

[0559]

[0668] Step 3 product: 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propanal (29 mg, 99%). LCMS; C 16 H 16 N2O4 theoretical value: 300, measured value: m / z = 301 [M+H] + .

[0560] Example 24B: Synthesis of 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butanal [ka]

[0670] Step 1 product: 3-(4-(4-hydroxybut-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (325 mg, 58.1%). LCMS: C 17 H 16 N2O4 theoretical value: 312, measured value: m / z = 313 [M+H] + .

[0561]

[0671] Step 2 product: 3-(4-(4-hydroxybutyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (244 mg, 74.1%). LCMS: C 17 H 20 N2O4 theoretical value: 316, measured value: m / z = 317 [M+H] + .

[0562]

[0672] Step 3 product: 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butanal (178 mg, 73.4%). LCMS: C 17 H 18 N2O4 theoretical value: 314, measured value: m / z = 315 [M+H] + .

[0563] Example 25: Synthesis of 2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propoxy)acetaldehyde [ka] Step 1: 3-Bromo-2-methylbenzoic acid

[0675] A mixture of methyl 3-bromo-2-methylbenzoate (35.0 g, 152.79 mmol) and LiOH (10.9 g, 453.79 mmol) in THF (300 mL) and HO (50 mL) was stirred at 60 °C for 16 h and then concentrated in vacuo. The residue was diluted with water (80 mL), and the mixture was acidified to pH 4 with 2 N HCl. The precipitated solid was collected by filtration and washed with water. The solid was dried in vacuo to give 3-bromo-2-methylbenzoic acid (30 g, 91%) as a white solid. (C8H7BrO2) [M+H] + MS(ESI) calculated for 214.9, 216.9; found for 215.0, 217.0.

[0564] Step 2: 3-Bromophthalic Acid

[0677] To a solution of KOH (78.3 g, 1395.58 mmol) in HO (2.5 L) was added 3-bromo-2-methylbenzoic acid (50.0 g, 232.51 mmol) at room temperature. The mixture was stirred for 5 minutes, and then KMnO (73.5 g, 465.02 mmol) was added to the mixture. The resulting mixture was stirred at 70 °C for 16 hours. The mixture was cooled to room temperature and diluted with ethanol (1.0 L). The resulting mixture was stirred for an additional 30 minutes and then filtered. The filtrate was acidified to pH 4 with HCl (3 N) and extracted with ethyl acetate (1 L x 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give 3-bromophthalic acid (55 g, 96%) as an off-white solid. (C8H5BrO4) [M+H] + MS(ESI) calculated for 244.9, 246.9; found for 245.1, 247.1.

[0565] Step 3: 4-Bromoisobenzofuran-1,3-dione

[0679] A mixture of 3-bromophthalic acid (55.0 g, crude) in AcO (500 mL) was stirred at 140 °C for 2 h and then concentrated in vacuo. The residue was purified by trituration with ethyl acetate / petroleum ether (1 / 5) to give 4-bromophthalic acid. Isobenzofuran-1,3-dione (45 g, crude) was obtained as a pale yellow solid. (C8H3BrO3) [M+H] + MS(ESI) calculated for 226.9, 228.9; found for 227.1, 229.1.

[0566] Step 4: tert-Butyl 3-bromo-5-methyl-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

[0681] A mixture of 4-bromoisobenzofuran-1,3-dione (15.0 g, 66.08 mmol), 3-aminopiperidine-2,6-dione hydrochloride (15.2 g, 92.50 mmol), and NaOAc (9.2 g, 112.33 mmol) in AcOH (200 mL) was stirred at 140° C. for 8 hours under a nitrogen atmosphere. The mixture was cooled to room temperature. The solid was collected by filtration and washed with water and ethyl acetate. The solid was dried under vacuum to give 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (20 g, 89%) as an off-white solid. (C 13 H9BrN2O4)[M+H] + MS(ESI) calculated values ​​for 336.9, 338.9.

[0567] Step 5: 2-(2,6-dioxopiperidin-3-yl)-4-(3-(2-hydroxyethoxy)prop-1-yn-1-yl)isoindoline-1,3-dione

[0683] To a degassed solution of 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (10.0 g, 29.66 mmol) in dry N,N-dimethylformamide (160 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (3.1 g, 4.44 mmol), copper(I) iodide (1.4 g, 7.36 mmol), N-ethyl-N-isopropylpropan-2-amine (100 mL), and 2-(prop-2-yn-1-yloxy)ethan-1-ol (4.4 g, 44.34 mmol). The resulting mixture was stirred under nitrogen at 80°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 0-100% ethyl acetate in petroleum ether to give 2-(2,6-dioxopiperidin-3-yl)-4-(3-(2-hydroxyethoxy)prop-1-yn-1-yl)isoindoline-1,3-dione (3.0 g, 28%) as a gray solid. (C 18 H 16 N2O6)[M+H] + MS(ESI) calculated for 357.1; found 357.0.

[0568] Step 6: 2-(2,6-dioxopiperidin-3-yl)-4-(3-(2-hydroxyethoxy)propyl)isoindoline-1,3-dione

[0685] A mixture of 2-(2,6-dioxopiperidin-3-yl)-4-(3-(2-hydroxyethoxy)prop-1-yn-1-yl)isoindoline-1,3-dione (2.8 g, 7.87 mmol) and palladium / C (0.7 g, 10%) in ethyl acetate (50 mL) was stirred under H2 at room temperature for 16 hours. The solid was filtered. The filtrate was concentrated in vacuo to give the crude product. The residue was purified by reverse-phase flash column chromatography using 5-50% acetonitrile in water to give 2-(2,6-dioxopiperidin-3-yl)-4-(3-(2-hydroxyethoxy)propyl)isoindoline-1,3-dione (882.2 mg, 31%) as a white solid. (C 18 H 20 N2O6)[M+H] + MS(ESI) calculated for 361.1; found 361.1.

[0569] Step 7: 2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propoxy)acetaldehyde

[0687] 1,1-Bis(acetyloxy)-3-oxo-3H-1λ5,2-benziodaoxol-1-yl acetate (90 mg, 0.21 mmol) was added to a mixture of 3-[4-(3-hydroxypropyl)-1-oxo-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (32 mg, 0.11 mmol) and CHCl (1 mL). The mixture was stirred at room temperature for 1 h. The mixture was purified by MPLC (10 to 100% EtOAc in hexanes) to give 2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propoxy)acetaldehyde (35 mg, 97%).

[0570] Example 26: Synthesis of 4-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-ylamino)-1,3,4-oxadiazol-2-yl)butanoic acid [ka] Step 1: 5-(benzyloxy)-5-oxopentanoic acid

[0690] To a solution of dihydro-3H-pyran-2,6-dione (50.0 g, 438.21 mmol) in toluene (500 mL) was added phenylmethanol (52.1 g, 482. 40 mmol) was added. The resulting solution was stirred at 70° C. for 48 hours. Upon completion of the reaction, the resulting mixture was concentrated in vacuo to give 5-(benzyloxy)-5-oxopentanoic acid (90 g, crude) as a colorless oil, which was used in the next step without further purification. (C 12 H 14 O4) [M+H] + MS(ESI) calculated for 223.1; found 223.0.

[0571] Step 2: tert-Butyl 2-(5-(benzyloxy)-5-oxopentanoyl)hydrazinecarboxylate

[0692] To a solution of 5-(benzyloxy)-5-oxopentanoic acid (20.0 g, 89.99 mmol) in DMF (500 mL) was added tert-butyl hydrazine carboxylate (11.9 g, 89.99 mmol), DIEA (58.1 g, 449.96 mmol), and HATU (68.4 g, 179.99 mmol). The mixture was stirred at 0 °C for 1.5 h. Upon completion of the reaction, the resulting mixture was diluted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel flash column chromatography using 0 to 50% ethyl acetate in petroleum ether to give tert-butyl 2-(5-(benzyloxy)-5-oxopentanoyl)hydrazine carboxylate (28.0 g, 92%) as a yellow oil. (C 17 H 24 N2O5)[M+H] + MS(ESI) calculated for 337.2; found [M+Na] + , 359.2.

[0572] Step 3: Benzyl 5-hydrazinyl-5-oxopentanoate

[0694] To a solution of tert-butyl 2-(5-(benzyloxy)-5-oxopentanoyl)hydrazinecarboxylate (18.0 g, 54.05 mmol) in CHCl (100 mL) was added TFA (50 mL). The mixture was stirred at room temperature for 16 hours. Upon completion of the reaction, the reaction solution was concentrated in vacuo. The residue was dissolved in saturated aqueous NaHCO and extracted with dichloromethane. The combined organic phase was washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give benzyl 5-hydrazinyl-5-oxopentanoate (12.0 g, crude) as a yellow oil, which was used in the next step without further purification. (C 12 H 16 N2O3)[M+H] + MS(ESI) calculated for 237.1; found 237.1.

[0573] Step 4: Benzyl 4-(5-amino-1,3,4-oxadiazol-2-yl)butanoate

[0696] To a solution of benzyl 5-hydrazinyl-5-oxopentanoate (13.5 g, 57.14 mmol) in MeOH (200 mL) was added carbonitridic bromide (7.3 g, 68.56 mmol). The mixture was stirred at 60° C. for 4 h. After the reaction was complete, the mixture was concentrated under vacuum. The residue was dissolved in saturated aqueous NaHCO3 and extracted with dichloromethane. The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel flash column chromatography using 0-100% ethyl acetate in petroleum ether to give benzyl 4-(5-amino-1,3,4-oxadiazol-2-yl)butanoate (8.0 g, 53%) as a white solid. (C 13 H 15 N3O3)[M+H] + MS(ESI) calculated for 262.1; found 262.1.

[0574] Step 5: 3-(1-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)piperidine-2,6-dione

[0698] To a degassed solution of 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.0 g, 3.09 mmol) in dioxane (10 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.57 g, 6.1 mmol). To the resulting solution, Pd(dppf)Cl2 (226 mg, 0.31 mmol), Pd(dppf)Cl2 (226 mg, 0.31 mmol), and KOAc (607 mg, 6.19 mmol) were added. The mixture was stirred under nitrogen at 90 °C for 16 hours. Upon completion of the reaction, the solid was filtered off. The filtrate was concentrated under vacuum. The residue was purified by silica gel flash column chromatography using 0 to 100% ethyl acetate in petroleum ether to give 3-(1-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-isoindolin-2-yl)piperidine-2,6-dione (1.2 g, 83%) as a yellow solid. (C 19 H 23 BN2O5)[M+H] + MS(ESI) calculated for 370.2; found 370.1.

[0575] Step 6: 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-ylboronic acid

[0700] To a solution of 3-[1-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (1.0 g, 2.75 mmol) in THF (48 mL) and HO (12 mL) was added NaIO (2.1 g, 10.00 mmol). The mixture was stirred at room temperature for 30 minutes. Then, 1 N HCl (1.9 mL, 1.90 mmol) was added to the above mixture, which was then stirred at room temperature for an additional 4 hours. Upon completion of the reaction, the solid was filtered off. The filtrate was concentrated in vacuo. The residue was purified by reverse-phase FC using 5-60% MeCN in HO to give 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-ylboronic acid (410 mg, 51%) as an off-white solid. 13 H 13 BN2O5)[M+H] + MS(ESI) calculated for 289.1; found 289.1.

[0576] Step 7: Benzyl 4-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-ylamino)-1,3,4-oxadi-azol-2-yl)butanoate

[0702] To a solution of 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-ylboronic acid (310 mg, 1.07 mmol) in CHCl (6 mL) was added benzyl 4-(5-amino-1,3,4-oxadiazol-2-yl)butanoate (525 mg, 2.01 mmol), Cu(OAc) (224 mg, 1.24 mmol), TEA (1.5 mL), and 4A MS (100 mg). The mixture was stirred under oxygen at room temperature for 16 hours. Upon completion of the reaction, the solid was filtered. The filtrate was concentrated in vacuo. The residue was purified by reverse-phase FC using 5-65% MeCN in HO to give benzyl 4-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-ylamino)-1,3,4-oxadiazol-2-yl)butanoate (370 mg, 68%) as a yellow solid. (C 26 H 25N5O6)[M+H] + MS(ESI) calculated for 504.2; found 504.4.

[0577] Step 8: 4-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-ylamino)-1,3,4-oxadiazol-2-yl)-butanoic acid

[0704] To a solution of benzyl 4-(5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-ylamino)-1,3,4-oxadiazol-2-yl)butanoate (360 mg, 0.71 mmol) in ethyl acetate (5 mL) was added Pd / C (dry, 50 mg). The mixture was stirred under hydrogen at room temperature for 16 hours. Upon completion of the reaction, the solid was filtered off. The filtrate was concentrated in vacuo. The residue was purified by reversed-phase FC using 5-55% MeCN in HO and then further purified by prep-HPLC using the following conditions: [Column: Sunfire prep C18 column 30*150, 5um; Mobile phase A: Mobile phase B: ACN; Flow rate: 60mL / min; Gradient: 10% B to 26% B in 7 min; 254nm] to give 4-(5-(2-(2,6-dioxopiperidine-3- To the resulting mixture was obtained (25 mg, 8%) of 1-oxoisoindolin-4-ylamino)-1,3,4-oxadiazol-2-yl)-butanoic acid as a white solid. (C 19 H 19 N5O6)[M+H] + MS(ESI) calculated for 414.1; found 414.4. 1 H NMR(400MHz,DMSO-d6)δ12.17(s,1H),11.04(s,1H),10.23(s,1H),8.17-8.13(m,1H),7.54(t,J=7.6Hz,1H),7.42(d,J=7.6Hz,1H),5.17-5.12 (m,1H),4.63-4.28(m,2H),2.97-2.91(m,1H),2.84-2.79(m,2H),2.66 -2.59(m,1H),2.41-2.24(m,3H),2.13-2.00(m,1H),1.96-1.85(m,2H).

[0578] Example 27: General Procedure G [ka]

[0706] Step 1: 3-(4-Bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (4.6 mmol), copper iodide (177 mg), and bis-triphenylphosphine-palladium dichloride (326 mg) were evacuated and flushed with nitrogen three times. DMF (5 mL), triethylamine (6.5 mL), and alkyne (27.9 mmol) were added, and the vial was flushed with nitrogen, sealed, and heated to 80 °C for 20 h. The mixture was cooled to room temperature, diluted with DCM / ethyl acetate (1:1, 20 mL), and the solid was filtered through a pad of Celite. The solid was stirred with acetonitrile for 16 h. The solid was filtered and concentrated to give the disubstituted alkyne product.

[0579]

[0707] Step 2: Disubstituted alkyne (2.2 mmol) was dissolved in methanol (40 mL). Palladium over charcoal (10%, 235 mg) was added. After addition, the flask was charged with hydrogen at 65 psi for 3 hours. The mixture was filtered through celite and washed with methanol to give the alcohol product.

[0580]

[0708] Step 3: Chromic acid (360 mg, 3.6 mmol) was added to 3 M sulfuric acid (3 mL) to prepare a solution of chromium oxidant (Jones reagent). Alcohol (1.2 mmol) was suspended in acetone (2.5 mL) and 3 M sulfuric acid (0.5 mL), and the suspension was cooled to 0°C. Jones reagent was slowly added to the alcohol suspension and stirred for 1 hour. The mixture was poured into ice water (20 mL), and the solid was filtered and washed with water. The aqueous solution (2 x 20 mL) with EtOAc, washed with brine and concentrated. The organic fraction was combined with the solid and the mixture was purified by flash column chromatography (0-25% methanol in DCM) to give the acid product.

[0581] Example 27A: Synthesis of 5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentanoic acid [ka]

[0710] Step 1 product: 3-(4-(5-hydroxypent-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (325 mg, 58%). LCMS: C 18 H 18 N2O4 theoretical value: 326, measured value: m / z = 349 [M+Na] + .

[0582]

[0711] Step 2 product: 3-(4-(5-hydroxypentyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (160 mg, 99%). LCMS: C 18 H 22 N2O4 theoretical value: 330, measured value: m / z = 353 [M+Na] + .

[0583]

[0712] Step 3 product: 5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentanoic acid (74 mg, 60%). LCMS; C 18 H 20 N2O5 theoretical value: 344, measured value: m / z = 367 [M+Na] + .

[0584] Example 28: Synthesis of 3-(3-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)propoxy)propanoic acid [ka] Step 1: Methyl 5-bromo-2-(bromomethyl)benzoate

[0715] To a solution of methyl 5-bromo-2-methylbenzoate (24.5 g, 107.4 mmol) in CCl4 (300 mL) was added NBS (17.1 g, 96.7 mmol) and BPO (4.8 g, 19.8 mmol). The mixture was stirred at 80 °C under N2 for 16 h. The resulting mixture was cooled to room temperature and then filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel flash column chromatography using 0-5% ethyl acetate in petroleum ether to give methyl 5-bromo-2-(bromomethyl)benzoate (23.5 g, 76%) as a yellow oil. 1H NMR(300MHz,DMSO-d6)δ 7.98(d,J=2.1Hz,1H),7.81(dd,J=8.4,2.1Hz,1H),7.56(d,J=8.4Hz,1H),4.98(s,2H),3.88(s,3H).

[0585] Step 2: 3-(6-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0717] Methyl 5-bromo-2-(bromomethyl)benzoate in MeCN (250 mL) To a mixture of ate (23.5 g, 76.8 mmol), 3-aminopiperidine-2,6-dione hydrochloride (19.0 g, 115.8 mmol) and TEA (31.0 g, 306.9 mmol) were added. The mixture was stirred at 80 °C for 16 hours. The resulting mixture was cooled to room temperature and then filtered. The filtrate was concentrated in vacuo, and the crude residue was purified by trituration with methanol and acetonitrile to give 3-(6-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (5.8 g, 23%) as a dark blue solid. 1 H NMR(300MHz,DMSO-d6)δ11.01(s,1H),7.91-7.78(m,2H),7.61(d,J=8.1Hz,1H),5.13(dd,J=13.2,5.1Hz,1H),4.46(d, J=17.7Hz,1H),4.32(d,J=17.7Hz,1H),2.98-2.86(m,1H),2.67-2.54(m,1H),2.47-2.33(m,1H),2.08-1.99(m,1H).(C 13 H11 BrN2O3)[M+H] + MS(ESI) calculated for 323.0 / 325.0; found 322.9 / 324.9.

[0586] Step 3: tert-Butyl 3-((3-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)prop-2-yn-1-yl)oxy)propanoate

[0719] 3-(6-Bromo-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (511 mg, 1.58 mmol), (PPh3)2PdCl2 (66.6 mg, 0.09 mmol), and CuI (30.1 mg, 0.16 mmol) were added to a vial. The vial was evacuated and backfilled with N2 five times. DMF (5 mL), tert-butyl 3-(prop-2-yn-1-yloxy)propanoate (437 mg, 2.37 mmol), and triethylamine (2.64 mL, 19.0 mmol) were added, and the mixture was stirred at 90 °C overnight. The mixture was filtered through Celite and washed with MeOH and EtOAc. The volatiles were removed under vacuum. EtOAc and H2O were added. The organic layer was washed with brine, dried over MgSO, filtered, concentrated, and purified by MPLC (0-10% MeOH in CHCl) to give tert-butyl 3-({3-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]prop-2-yn-1-yl}oxy)propanoate (107 mg, 15.9%). LCMS: C 23 H 26 N2O6 theoretical value: 426, measured value: m / z = 427 [M+H] + .

[0587] Step 4: tert-butyl 3-(3-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)propoxy)propanoate

[0721] A mixture of tert-butyl 3-({3-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]prop-2-yn-1-yl}oxy)propanoate (107 mg, 0.25 mmol), Pd / C 10 wt% (2.5 mg, 0.03 mmol), and EtOH (4 mL) was mixed in a flask. The flask was evacuated and backfilled with H2 five times and stirred at room temperature for 2 hours. The mixture was filtered through Celite, washed with MeOH and EtOAc, concentrated, and carried to the next step. LCMS: C 23 H 30 N2O6 theoretical value: 430, measured value: m / z = 431 [M+H] + .

[0588] Step 5: 3-(3-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)propoxy)propanoic acid

[0723] A mixture of tert-butyl 3-{3-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]propoxy}propanoate (106 mg, 0.25 mmol), CHCl (2 mL), and trifluoroacetic acid (0.4 mL) was stirred at room temperature for 2 hours. The volatiles were removed to give 3-{3-[2-(2,6-dioxopiperidin-3-yl)-3-oxo-1H-isoindol-5-yl]propoxy}propanoate. {propoxy}propanoic acid (60 mg, 65.1% over two steps) was obtained. LCMS: C 19 H 22 N2O6 theoretical value: 374, measured value: m / z = 375 [M+H] + .

[0589] Example 29: Synthesis of 4-((2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione [ka]

[0725] Step 1: A solution of tert-butyl N-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethyl]carbamate (3 g, 10.26 mmol, 1 equiv.), i-PrNEt (2.65 g, 20.52 mmol, 3.57 mL, 2 equiv.), and 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (2.89 g, 10.26 mmol, 1 equiv.) in DMSO (40 mL) was stirred at 90 °C for 6 h. The reaction mixture was diluted with HO (60 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by reverse MPLC column (0.1% FA in HO). tert-Butyl N-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]carbamate (2.9 g, 5.29 mmol, 51.5%) was obtained as a blue oil. LCMS: C 26 H 36 N4O9 theoretical value: 548, measured value: m / z = 549 [M+H] + .

[0590]

[0726] Step 2: A solution of tert-butyl N-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]carbamate (2.9 g, 5.29 mmol, 1 equiv.) and HCl (4 M in dioxane, 30 mL, 22.7 equiv.) was stirred at 25 °C under N for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by HPLC (1-30% MeCN in HO containing 0.05% HCl). 4-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (1.1 g, 2.07 mmol, 39.1%, 2HCl) was obtained as a yellow solid. LCMS: C 21 H 28 N4O7 theoretical value: 448, measured value: m / z = 449 [M+H] + .

[0591] Example 30: Synthesis of 3-[4-[3-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]propyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione [ka]

[0728] Step 1: A mixture of 3-(4-bromo-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (2.52 mmol), (PPh3)2PdCl2 (0.15 mmol), CuI (0.25 mmol), and alkyne (5.04 mmol) was added to a vial. The vial was evacuated and backfilled with N2 five times. DMF and triethylamine (30.3 mmol) were added, and the mixture was stirred at 90 °C overnight. The mixture was filtered through Celite and washed with MeOH and EtOAc. EtOAc and saturated aqueous NaCl were added. The organic layer was dried over MgSO4, filtered, concentrated, and purified by reverse-phase MPLC (5-100% MeCN in HO on a C18 column) to give the product.

[0592]

[0729] Step 2: A mixture of disubstituted alkyne (0.81 mmol), Pd / C 10 wt% (0.08 mmol), and EtOH was mixed in a flask. The flask was evacuated and backfilled with H2 five times and stirred at room temperature for 2 h. The mixture was filtered through Celite, washed with MeOH and EtOAc, concentrated, and carried to the next step.

[0593]

[0730] Step 3: A mixture of tert-butyl carbamate (0.81 mmol), CH2Cl2 (2 mL), and TFA (2 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to give the amine product.

[0594]

[0731] Step 1 product: tert-butyl N-[2-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]prop-2-ynoxy]ethoxy]ethoxy]ethyl]carbamate (1.45 g, 58.1%). LCMS: C 27 H 35 N3O8 theoretical value: 529, measured value: m / z = 552 [M+Na] + .

[0595]

[0732] Step 2 product: tert-butyl N-[2-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]propoxy]ethoxy]ethoxy]ethyl]carbamate (960 mg, 92.75%). LCMS: C 27 H 39 N3O8 theoretical value: 533, measured value: m / z = 556 [M+Na] + .

[0596]

[0733] Step 3 product: 3-[4-[3-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]propyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (576.82 mg, 74.15%). LCMS: C 22 H 31 N3O6 theoretical value: 433, measured value: m / z = 434 [M+H] + .

[0597] Example 31: Synthesis of 5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]-3-{[4-(piperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide Step 1: 2-(2,6-dioxopiperidin-3-yl)-5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]isoindole-1,3-dione [ka]

[0736] A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (373 mg, 1.35 mmol), DMF (8 mL), ethylbis(propan-2-yl)amine (0.94 mL, 5.40 mmol), and prolinol (137 mg, 1.35 mmol) was stirred at 90 °C for 16 h. CHCl and HO were added. The organic layer was dried over MgSO, filtered, concentrated, and purified by MPLC (0–10% MeOH in CHCl) to give 2-(2,6-dioxopiperidin-3-yl)-5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]isoindole-1,3-dione (386.00 mg, 80.0%).

[0598] Step 2: (2S)-1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]pyrrolidine-2-carbaldehyde [ka]

[0738] 1,1-Bis(acetyloxy)-3-oxo-1λ5,2-benziodaoxol-1-yl acetate (548 mg, 1.29 mmol) was added to a mixture of 3-{5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-1-oxo-3H-isoindol-2-yl}piperidine-2,6-dione (222 mg, 0.65 mmol) and CHCl (10 mL). The mixture was stirred at room temperature for 1 h. The mixture was purified by MPLC (10 to 100% EtOAc in hexanes) to give (2S)-1-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]pyrrolidine-2-carbaldehyde (67 mg, 30%).

[0599] Example 32: Synthesis of 5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]-3-{[6-(piperazin-1-yl)pyridin-3-yl]amino}pyrazine-2-carboxamide [ka] Step 1: tert-butyl 4-[5-({3-cyano-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)pyridin-2-yl]piperazine-1-carboxylate

[0741] A mixture of 3-chloro-5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2-carbonitrile (322 mg, 1.00 mmol), tert-butyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylate (293 mg, 1.05 mmol), (acetyloxy)paradioacetate (74 mg, 0.33 mmol), [2'-(diphenylphosphanyl)-[1,1'-binaphthalen]-2-yl]diphenylphosphane (206.27 mg, 0.33 mmol), and CsCO (981 mg, 3.01 mmol) was degassed and backfilled with N five times. The mixture was stirred at 100 °C for 90 min. The mixture was filtered through Celite, washed with MeOH / EtOAc, concentrated, and purified by MPLC (0-100% EtOAc in CHCl) to give tert-butyl 4-[5-({3-cyano-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)pyridin-2-yl]piperazine-1-carboxylate (0.2920 g, 51.7%).

[0600] Step 2: tert-Butyl 4-[5-({3-carbamoyl-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)pyridin-2-yl]piperazine-1-carboxylate

[0743] HO (30% in water, 0.88 mL, 0.09 mmol) was added to a mixture of rac-tert-butyl 4-[5-({3-cyano-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)pyridin-2-yl]piperazine-1-carboxylate (292 mg, 0.52 mmol), CsCO (169 mg, 0.52 mmol), DMSO (0.5 mL), and MeOH (10 mL). The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated. EtOAc was added, and the organic phase was washed with HO and brine. The organic layer was dried over MgSO4, filtered, concentrated, and purified by MPLC (0-10% MeOH in CH2Cl2) to give tert-butyl 4-[5-({3-carbamoyl-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazine-2 -yl}amino)pyridin-2-yl]piperazine-1-carboxylate (0.279 g, 92.6%) was obtained.

[0601] Step 3: 5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]-3-{[6-(piperazin-1-yl)pyridin-3-yl]amino}pyrazine-2-carboxamide

[0745] A mixture of tert-butyl 4-[5-({3-carbamoyl-6-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]pyrazin-2-yl}amino)pyridin-2-yl]piperazine-1-carboxylate (279 mg, 0.48 mmol), CHCl (5 mL), and TFA (1 mL) was stirred at room temperature for 2 hours. The volatiles were removed. The mixture was filtered through a NaHCO cartridge, concentrated, and purified by reverse-phase MPLC (5-90% MeCN in HO) to give 5-[(3R)-3-(3-methyl-2-oxoimidazolidin-1-yl)piperidin-1-yl]-3-{[6-(piperazin-1-yl)pyridin-3-yl]amino}pyrazine-2-carboxamide (0.085 g, 37%).

[0602] Example 33: Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)azetidine-3-carbaldehyde [ka]

[0747] Step 1: TFA (1 mL) was added to a solution of tert-butyl 3-[(benzyloxy)methyl]azetidine-1-carboxylate (1 g, 3.62 mmol, 1.1 equiv.) in CHCl (1 mL). After stirring for 30 min, the reaction mixture was concentrated under reduced pressure and carried on to the next step.

[0603]

[0748] Step 2: 5-Fluoro-3H-2-benzofuran-1-one (500 mg, 3.29 mmol, 1 equiv.) and i-PrNEt (2.86 mL, 16.4 mmol, 5 equiv.) were added sequentially to a solution of the crude amine in NMP (4 mL). The reaction mixture was heated at 100 °C for 16 h. After stirring for 1 h, the reaction was quenched with H2O. The resulting mixture was extracted with EtOAc, dried over Na2SO4, and concentrated under reduced pressure. MPLC (0-30% EtOAc in hexanes) afforded the desired product (848 mg, 2.74 mmol, 83% yield). LCMS: C 19 H 19 NO3 theoretical value: 309, measured value: m / z = 310 [M+H] + .

[0604]

[0749] Step 3: A solution of NaOH (439 mg, 11 mmol, 4 equiv) in HO (1.8 mL) was added to a solution of 5-{3-[(benzyloxy)methyl]azetidin-1-yl}-3H-2-benzofuran-1-one (848 mg, 2.74 mmol, 1 equiv) in MeOH (3.4 mL) and THF (3.4 mL). After stirring for 1 h, the volatiles were removed. The resulting mixture was diluted with HO and extracted with EtOAc. The aqueous phase was acidified to pH 6 with 1.5 N aqueous HCl, extracted with EtOAc, dried over NaSO, concentrated under reduced pressure, and carried to the next step. (659 mg, 2.01 mmol, 73% yield). LCMS: C 19 H 21 NO4 theoretical value: 327, measured value: m / z = 328 [M+H] + .

[0605]

[0750] Step 4: Dess-Martin periodinane (774 mg, 1.83 mmol, 1.1 equiv) was added to a solution of 4-{3-[(benzyloxy)methyl]azetidin-1-yl}-2-(hydroxymethyl)benzoic acid (543 mg, 1.66 mmol, 1 equiv) in CHCl (8.3 mL). After stirring for 1 h, the reaction was quenched with an equal mixture of saturated aqueous NaHCO and 10 wt.% NaSO. After stirring for 30 min, the resulting mixture was extracted with CHCl, dried over NaSO, and concentrated under reduced pressure. MPLC (0-5% MeOH in CHCl) afforded the desired product (435 mg, 1.34 mmol, 81% yield). LCMS: C 19 H 19 NO4 theoretical value: 325, measured value: m / z = 326 [M+H] + .

[0606]

[0751] Step 5: NaOAc (203 mg, 2.48 mmol, 1.5 equiv) and NaBHCN (311 mg, 4.94 mmol, 3 equiv) were added sequentially to a solution of 3-aminopiperidine-2,6-dione hydrochloride (407 mg, 2.48 mmol, 1.5 equiv) and 4-(3-((benzyloxy)methyl)azetidin-1-yl)-2-formylbenzoic acid (536 mg, 1.65 mmol, 1 equiv) in MeOH (8.2 mL). After stirring for 30 min, the reaction mixture was concentrated un...

Claims

1. Formula (A) 【Chemical 1】 (In the formula, W is CH; D is a bond or —NH—; Ring A is phenyl, a 9- to 10-membered bicyclic aryl, a 5- to 6-membered partially or fully unsaturated monocyclic heterocycle, or a 9- to 10-membered bicyclic heteroaryl, wherein the monocyclic heterocycle and bicyclic heteroaryl of Ring A each have 1 to 3 heteroatoms independently selected from N, O, and S, and Ring A is optionally and independently selected from halo, —CN, —COOH, NH ２ and optionally substituted C １～６ substituted by up to three substituents selected from alkyl; Ring B is phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, or 8-10 membered spiro bicyclic heterocycle, wherein Ring B is optionally substituted, and said heteroaryl and heterocycloalkyl of Ring B have 1-3 heteroatoms independently selected from N, O, and S; L is -X １ -X ２ -X ３ -X ４ -X ５ - and; X １ represents a bond, —C(O)—, —C(O)—N(R)—, —N(R)—C(O)—, —(O—CH ２ -CH ２ ) ｍ -, -O(C ６ H ４ ) -, -(O-CH ２ -CH ２ -CH ２ ) ｍ -, -C １～５ alkyl-, a 7- to 12-membered spiro or fused bicyclic heterocycloalkyl having 1 to 3 heteroatoms independently selected from N, O, and S, or a 4- to 6-membered monocyclic heterocycloalkyl having 1 to 2 heteroatoms independently selected from N, O, and S; and X １ Each of said monocyclic and bicyclic heterocycloalkyls is -CH ３ and optionally substituted by X ２ is a bond, -(O-CH ２ -CH ２ ) ｎ -, -(CH ２ -CH ２ -O) ｎ -, -N(R)-C(O)-, -N(R)-, -C(O)-, -C(O)-N(R)-, -C １～５ alkyl-, a 4- to 6-membered monocyclic cycloalkyl, or a 4- to 6-membered monocyclic heterocycloalkyl having 1-2 heteroatoms independently selected from N, O, and S; X ３ is a bond, -C １～８ Alkyl-, —C≡C—, 4- to 6-membered cycloalkyl, —N(R)—, —N(R)—C(O)—, —(O—CH ２ -CH ２ ) ｐ -, -(CH ２ -CH ２ -O) ｐ a 4- to 6-membered heterocycloalkyl having 1 to 2 heteroatoms independently selected from —, N, O, and S, wherein said heterocycloalkyl is —CH ３ and optionally substituted by X ４ is a bond, -CH ２ -CH ２ -N(R)-, -N(R)-, -C １～４ Alkyl-, -(O-CH ２ -CH ２ -CH ２ ) ｍ -, a 5-6 membered saturated, partially unsaturated, or fully unsaturated carbocyclic ring or a 5-6 membered saturated, partially unsaturated, or fully unsaturated heterocyclic ring having 1 to 3 heteroatoms independently selected from N, O, and S; X ５ is a bond, -C １～４ alkyl-, —N(R)—, —O—, —C(O)—, or —C(O)—N(R)—; Each R is independently —H or —C １～３ alkyl; and each of m, n, and p is independently an integer from 1 to 3; and Y is a group represented by any one of the following formulae: 【Chemistry 2】 is) or a pharmaceutically acceptable salt thereof.

2. 10. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, vehicle, or adjuvant.

3. 10. The compound or pharmaceutically acceptable salt thereof according to claim 1, for treating a disease or disorder mediated by the degradation of Bruton's tyrosine kinase, wherein the disease or disorder is cancer.

4. 4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein the cancer is a blood cancer selected from myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), hairy cell, mantle cell lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphoma, and follicular lymphoma.

5. A compound or a pharmaceutically acceptable salt thereof according to claim 1 for treating a disease or disorder mediated by degradation of Bruton's tyrosine kinase, wherein the disease or disorder is an autoimmune disease.

6. The autoimmune disease is selected from the group consisting of urticaria, graft-versus-host disease, pemphigus vulgaris, achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, axonal and neuronal neuropathy (AMAN), Barrow's disease, Behcet's disease, benign mucous membrane pemphigoid, bullous pemphigoid Smallpox, Castleman's disease (CD), celiac disease, Chagas' disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulin Phosphatemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's disease, hemolytic anemia, Henoch-Schonlein purpura (HSP), herpes gestationis or pemphigoid of gestationis (PG), hidradenitis suppurativa (HS) (acne inversa), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes mellitus ( Type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, lignified conjunctivitis, linear immunoglobulin A disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Much-Habermann disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatoid arthritis (PR), PANDAS,Paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, II, III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progestational dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal gland 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, selected from fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm and testicular autoimmunity, stiff-person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia (SO), Takayasu's arteritis, temporal arteritis (giant cell arteritis), thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease, and Wegener's granulomatosis (or granulomatosis with polyangiitis (GPA)).

7. 7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein the autoimmune disease is selected from inclusion body myositis (IBM), polymyositis, dermatomyositis, granulomatosis with polyangiitis, and juvenile myositis (JM).

8. 7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein the autoimmune disease is selected from juvenile diabetes, Churg-Strauss syndrome (CSS), Coxsackie myocarditis, dermatitis herpetiformis, discoid lupus, neonatal lupus, undifferentiated connective tissue disease (UCTD), essential mixed cryoglobulinemia, IgA nephropathy, immune thrombocytopenic purpura, Henoch-Schonlein purpura (HSP), Kawasaki disease, microscopic polyangiitis (MPA), polyarteritis nodosa, Takayasu's arteritis, pemphigus vulgaris, and perivenous encephalomyelitis.

9. A pharmaceutical composition as described in claim 2 for treating a disease or disorder mediated by the degradation of Bruton's tyrosine kinase, wherein the disease or disorder is cancer.

10. The pharmaceutical composition described in claim 9, wherein the cancer is a blood cancer selected from myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma) hairy cell, mantle cell lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphoma, and follicular lymphoma.

11. A pharmaceutical composition as described in claim 2 for treating a disease or disorder mediated by the degradation of Bruton's tyrosine kinase, wherein the disease or disorder is an autoimmune disease.

12. The autoimmune disease is selected from the group consisting of urticaria, graft-versus-host disease, pemphigus vulgaris, achalasia, Addison's disease, adult Still's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune autonomic neuropathy, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, axonal and neuronal neuropathy (AMAN), Barrow's disease, Behcet's disease, benign mucous membrane pemphigoid, and bullous Pemphigoid, Castleman's disease (CD), celiac disease, Chagas' disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn's disease, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoproliferative disorder Gammaglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis, Graves' disease, Guillain-Barré syndrome, Hashimoto's disease, hemolytic anemia, Henoch-Schonlein purpura (HSP), herpes gestationis or pemphigoid of gestationis (PG), hidradenitis suppurativa (HS) (acne inversa), hypogammaglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, lignified conjunctivitis, linear immunoglobulin A disease (LAD), lupus, chronic Lyme disease, Meniere's disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Much-Habermann disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatoid arthritis (PR),PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, type II, type III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progestational dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome ( 12. The pharmaceutical composition of claim 11, wherein the inflammatory bowel disease is selected from the group consisting of rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm and testicular autoimmunity, stiff-person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia (SO), Takayasu's arteritis, temporal arteritis (giant cell arteritis), thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), transverse myelitis, type 1 diabetes, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease, and Wegener's granulomatosis (or granulomatosis with polyangiitis (GPA)).

13. The pharmaceutical composition of claim 12, wherein the autoimmune disease is selected from inclusion body myositis (IBM), polymyositis, dermatomyositis, granulomatosis with polyangiitis, and juvenile myositis (JM).

14. The pharmaceutical composition of claim 12, wherein the autoimmune disease is selected from juvenile diabetes mellitus, Churg-Strauss syndrome (CSS), Coxsackie myocarditis, dermatitis herpetiformis, discoid lupus, neonatal lupus, undifferentiated connective tissue disease (UCTD), essential mixed cryoglobulinemia, IgA nephropathy, immune thrombocytopenic purpura, Henoch-Schonlein purpura (HSP), Kawasaki disease, microscopic polyangiitis (MPA), polyarteritis nodosa, Takayasu's arteritis, pemphigus vulgaris, and perivenous encephalomyelitis.

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