CYTOTOXICITY TARGETING CHIMERAS

1 . A compound of Formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

T is a target binding moiety;

R 1 is C 1-4 alkyl or C 3-6 cycloalkyl;

L is a divalent linker of Formula (L-a), (L-b), (L-c), (L-d), (L-e), (L-f), (L-g), (L-h), (L-i), (L-j), (L-k), (L-m), (L-n-i), (L-n-ii), (L-n-iii), or (L-n-iv):

 or a stereoisomer thereof,

wherein:

Ring A and Ring B are each independently C 4-6 cycloalkylene;

L 1a is C 3-5 linear alkylene, wherein 1 or 2 methylene units are replaced with —O— or —NR a —;

each R a is independently hydrogen or C 1-3 alkyl; and

L 2a is —O—, —NHC(O)—, or —CH 2 —O—;

 or a stereoisomer thereof,

wherein:

Ring A is C 4-6 cycloalkylene or C 7-9 bridged bicyclic cycloalkylene;

L 1b is —CH 2 —NH—C(O)—, —NHC(O)—, or —C(O)NH—;

L 2b is C 6-12 linear alkylene, wherein 1, 2, 3, or 4 methylene units are replaced with —O—, —NR 1b —, —C(O)NR 1b —, or —NR 1b C(O)—; or

L 2b is

 wherein n is 1, 2, 3, or 4, and

 represents a covalent bond to L 1b ; and

each R 1b is independently hydrogen or C 1-3 alkyl;

 or a stereoisomer thereof,

wherein:

L 1c is C 2-10 linear alkylene, wherein 1, 2, or 3 methylene units are replaced with —O—, —NH—, —NHC(O)—, or —C(O)NH—;

Ring A is C 4-6 cycloalkylene or C 7-9 bridged bicyclic cycloalkylene; and

L 2c is —O— or a saturated C 2-10 linear alkylene, wherein 1, 2, or 3 methylene units are replaced with —O—, —NH—, —NHC(O)—, or —C(O)NH—;

wherein:

L 1d is C 12-22 linear alkylene, wherein 1, 2, 3, 4, or 5 methylene units are replaced with —NH—, —O—, —C(O)NH—, —NHC(O)—, or —NHC(O)—NH—;

 wherein n is an integer of 3 to 50;

 or a stereoisomer thereof,

wherein:

L 1f is a bond; C 1-6 linear alkylene, wherein 0, 1, or 2 methylene units are replaced with —O—, —NH—, or —C(O)—; or —(C 3-6 cycloalkylene)-NHC(O)—;

L 2f is a bond, —NHC(O)—, —C(O)NH—, or a C 1-6 linear alkylene, wherein 0, 1, or 2 methylene units are replaced with —O—; and

each of Z 1 and Z 2 is independently N or CH;

wherein:

Ring A is a 5 to 6 membered heteroarylene having 1 or 2 nitrogen ring atoms;

L 1g is a bond, —CH 2 —, —NH—, or —O—; and

L 2g is

 wherein n is 1, 2, 3, 4, or 5, and

 represents a covalent bond to L 1g ;

 or a stereoisomer thereof,

wherein:

each Z 1 is independently N or CH;

L 1h is a bond, —C(O)—, —C(O)—NH—, or —NHC(O)—;

L 2h is C 2-10 linear alkylene or

 wherein n is 1, 2, 3, or 4, and

 represents a covalent bond to L 1h and

 represents a covalent bond to L 3h ;

L 3h is a bond, —C(O)CH 2 —, —O—(C 3-6 cycloalkylene)-O—, or —C(O)NH(CH 2 ) 3 OCH 2 —;

L 4h is a bond, —C(O)—, —CH 2 C(O)—, or —C(O)CH 2 —; and

m is 1, 2, or 3;

wherein:

L 1i is a bond, C 1-12 linear alkylene, or

 wherein n is 1, 2, 3, 4, or 5, and

 represents a covalent bond to L 3i and

 represents a covalent bond to NH;

L 2i is a bond, C 1-12 linear alkylene, or

 wherein n is 1, 2, 3, 4, or 5, and

 represents a covalent bond to HN; and

L 3i is a bond or —C(O)—;

 or a stereoisomer thereof,

wherein:

Z 1 is C, CH, or N;

each of Z 2 , Z 3 , Z 4 and Z 5 is independently CH or N, provided that no more than two of Z 2 , Z 3 , Z 4 and Z 5 are N;

L 1j is —NH—, —C(O)NH—, —NHC(O)—, or —O—;

L 2j is C 1-6 linear alkylene or

 wherein n is 1 or 2, and

 represents a covalent bond to L 1j ; and

represents a single bond or a double bond;

 or a stereoisomer thereof,

wherein:

Ring A is phenyl or a 5 or 6 membered heteroarylene having 1 or 2 nitrogen ring atoms;

each of Z 1 and Z 2 is independently CH or N;

L 1k is a bond, —C(O)—, —C(O)NH— or —NHC(O)—; and

L 2k is a C 3-8 straight chain alkylene or

 wherein n is 1, 2, or 3, and

 represents a covalent bond to L 1k ;

 or a stereoisomer thereof,

wherein:

Z 1 is CH or N;

m is 1 or 2;

p is 1 or 2;

0, 1, or 2 hydrogen atoms of

 are replaced with F;

L 1m is a bond, —C(O)—, —C(O)NH—, —NHC(O)—, —S(O) 2 NH— or —NHS(O) 2 —; and

L 2m is C 3-6 linear alkylene, C 3-6 cycloalkylene, or

 , wherein n is 1 or 2, and

represents a covalent bond to L 1m ;

wherein each

 represents a covalent bond to the Y group of Formula (I), or when Y is a bond, a covalent bond to the T group of Formula (I), and each

 represents a covalent bond to the methylene group of Formula (I); and

Y is a bond or a divalent spacer moiety of one to twelve atoms in length.

2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —CH 3 .

3 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker of Formula (L-a-i):

or a stereoisomer thereof,

wherein Ring A, L 1a , L 2a ,

 are as defined for Formula (L-a).

4 . The compound of any one of the preceding claims , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker of Formula (L-a-ii):

or a stereoisomer thereof,

wherein L 1a , L 2a ,

 are as defined for Formula (L-a); p is 1 or 2; and m is 1 or 2.

5 . The compound of any one of the preceding claims , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker of Formula (L-a-iii):

or a stereoisomer thereof,

wherein p is 1 or 2; m is 1 or 2; n is 1, 2, or 3; and

 are as defined for Formula (L-a).

6 . The compound of any one of claims 1 to 4 , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker of Formula (L-a) selected from the group consisting of:

7 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker of Formula (L-b-i):

or a stereoisomer thereof,

wherein L 1b , L 2b ,

 are as defined for Formula (L-b); p is 1 or 2; and m is 1 or 2.

8 . The compound of any one of claims 1, 2, or 7 , wherein L is a divalent linker of Formula (L-b) selected from the group consisting of:

9 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker of Formula (L-c-i):

or a stereoisomer thereof,

wherein L 1c , L 2c ,

 are as defined for Formula (L-c); p is 1 or 2; and m is 1 or 2.

10 . The compound of any one of claim 1 or 2 , wherein L is a divalent linker of Formula (L-c) selected from the group consisting of:

11 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker of Formula (L-d) selected from the group consisting of:

12 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker of Formula (L-f) selected from the group consisting of:

13 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker of Formula (L-g-i):

wherein L 1g , L 2g ,

 are as defined for Formula (L-g); Z 1 , Z 2 , and Z 3 are each independently selected from N or CH, provided that one or two of Z 1 , Z 2 , and Z 3 is N.

14 . The compound of any one of claims 1, 2, or 13 , wherein L is a divalent linker of Formula (L-g) selected from the group consisting of:

15 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker of Formula (L-h) selected from the group consisting of:

16 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker of Formula (L-i) selected from the group consisting of:

17 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker of Formula (L-j) selected from the group consisting of:

18 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker of Formula (L-k) selected from the group consisting of:

19 . The compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, wherein L is a divalent linker of Formula (L-m) selected from the group consisting of:

20 . The compound of any one of the preceding claims , or a pharmaceutically acceptable salt thereof, wherein Y is selected from a bond; —NH—; —(C 1-12 alkylene)-, wherein 1, 2, or 3 methylene units are replaced with —O—, —NH—, —C(O)—, NHC(O)—, —C(O)NH—, —(C 3-6 cycloalkylene)-, —(C 3-6 cycloalkenylene)-, 3- to 6-membered heterocycloalkylene, arylene, or heteroarylene; or —(C 2-12 alkenylene)-, wherein 1, 2, or 3 methylene units are replaced with —O—, —NH—, —C(O)—, NHC(O)—, —C(O)NH—, —(C 3-6 cycloalkylene)-, —(C 3-6 cycloalkenylene)-, 3- to 6-membered heterocycloalkylene, arylene, or heteroarylene.

21 . The compound of any one of the preceding claims , or a pharmaceutically acceptable salt thereof, wherein T is selected from the group consisting of:

22 . The compound of any one of the preceding claims , or a pharmaceutically acceptable salt thereof, wherein the target is selected from G protein-coupled receptor (GPCRs), enzymes, ion channels, proteases, and receptors.

23 . The compound of any one of the preceding claims , or a pharmaceutically acceptable salt thereof, wherein the target is present on a surface of a pathogenic immune cell, a tumor cell or cancer cell, or a stromal cell.

24 . The compound of any one of the preceding claims , wherein the target is present on the surface of a pathogenic agent selected from a virus or a bacterial cell.

25 . The compound of any one of the preceding claims , or a pharmaceutically acceptable salt thereof, wherein the target is present on a surface of monocytic myeloid-derived suppressor cells (mMDSCs), T regulatory cells (Tregs), neutrophils, macrophages, B regulatory cells (Bregs), CD8 regulatory cells, (CD8regs), exhausted T cells, polymorphonuclear myeloid derived suppressor cells (PMN-MDSCs), or cancer-associated fibroblasts (CAFs).

26 . The compound of any one of the preceding claims , or a pharmaceutically acceptable salt thereof, wherein the target is a chemokine receptor (CCR).

27 . The compound of any one of the preceding claims , wherein the target is selected from CCR1, CCR2, CCR3, or CCR5.

28 . The compound of any one of the preceding claims , wherein the target is selected from C-C motif chemokine receptor (CCR) 2 (CCR2), CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, CCR9, CCR10, C-X-C motif chemokine receptor 1 (CXCR1), C-X-C motif chemokine receptor 2 (CXCR2), C-X-C motif chemokine receptor 3 (CXCR3), C-X-C motif chemokine receptor 4 (CXCR4), C-X-C motif chemokine receptor 5 (CXCR5), C-X-C motif chemokine receptor 6 (CXCR6), atypical chemokine receptor 3 (ACKR3), integrin αvβ6, fibroblast activation protein-alpha (FAPα), prostate specific membrane antigen (PSMA), folate receptor (folate receptor 1 or folate receptor beta), complement C3a receptor 1 (C3AR1), complement C5a receptor 1 (C5AR1), G protein-coupled receptor (GPR) 65 (GPR65), GRP132, GPR84, GPR183, GPR35, GPR42, cholecystokinin A receptor (CCKAR), leukotriene B4 receptor (LTB4R), somatostatin receptor 2 (SSTR2), free fatty acid receptor 1 (FFAR1), purinergic receptor P2Y2 (P2RY2), prostaglandin D2 receptor (PTGDR), calcitonin receptor (CALCR), CD38, purinergic receptor P2X 7 (P2RX7), integrin subunit alpha V (ITGAV), integrin subunit alpha 5 (ITGA5), integrin subunit beta 1 (ITGB1), integrin subunit beta 6 (ITGB6), integrin subunit beta 3 (ITGB3) prostaglandin D2 receptor 2 (PTGDR2), gastrin releasing peptide receptor (GRPR), MER proto-oncogene tyrosine kinase (MERTK), C-X3-C motif chemokine receptor 1 (CX3CR1), oxidized low density lipoprotein receptor 1 (OLR1), plasminogen activator urokinase receptor (PLAUR), carbonic anhydrase 9 (CA9), carbonic anhydrase 12 (CA12), mas-related G-protein coupled receptor member X2 (MRGPRX2), heat shock protein 90 alpha family class A member 1 (HSP90AA1), dipeptidyl peptidase 4 (DPP4), formyl peptide receptor 2 (FPR2), and succinate receptor 1 (SUCNR1).

29 . A method of treating and/or preventing a disease or disorder in a patient in need thereof, the method comprising: administering to the patient a therapeutically effective amount of the compound of any one of the preceding claims and an anti-cotinine antibody, or antigen-binding fragment thereof, wherein the disease or disorder is selected from a cancer, an inflammatory disease, an autoimmune disease, a viral infection, or a bacterial infection.

30 . The method of claim 29 , wherein the disease or disorder is mediated by chemokine receptor 2 (CCR2) and/or is associated with CCR2-positive pathogenic cells.

31 . The method of claim 29 or 30 , wherein the disease is a cancer that is a solid tumor.

32 . The method of any one of claims 29 to 31 , wherein the cancer is selected from non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), colorectal cancer (CRC), cervical squamous cell carcinoma (CESC), head and neck squamous cell carcinoma (HNSC), pancreatic cancer, metastatic castration-resistant prostate cancer (mCRPC), ovarian cancer, bladder cancer, or breast cancer.

33 . The method of any one of claims 29 to 32 , wherein the compound and the antibody, or antigen-binding fragment thereof, are administered simultaneously.

34 . The method of any one of claims 29 to 32 , wherein the compound and the antibody, or antigen-binding fragment thereof, are administered sequentially.

35 . A method of increasing antibody-dependent cell cytotoxicity (ADCC) of target-expressing cells, the method comprising: contacting the cells with an effective amount of the compound of any one of claims 1 to 28 and an anti-cotinine antibody, or antigen-binding fragment thereof, wherein the target-binding moiety of the compound binds the target expressed on the cells.

36 . A method of depleting target-expressing cells, the method comprising: contacting the cells with an effective amount of the compound of any one of claims 1 to 28 and an anti-cotinine antibody, or antigen-binding fragment thereof, wherein the target-binding moiety of the compound binds the target expressed on the cells.

37 . The method of claim 35 or 36 , wherein the target-expressing cells are myeloid-derived suppressor cells (MDSCs), T regulatory cells (Tregs), neutrophils, macrophages, B regulatory cells (Bregs), CD8 regulatory cells, (CD8regs), exhausted T cells, or cancer-associated fibroblasts (CAFs).

38 . The method of any one of claims 29 to 37 , wherein the anti-cotinine antibody has a heavy chain and a light chain, the heavy chain comprising a CDR1 having SEQ ID NO: 1, a CDR2 having SEQ ID NO: 2, and a CDR3 having SEQ ID NO: 3, and the light chain comprising a CDR1 having SEQ ID NO: 4, a CDR2 having SEQ ID NO: 5, and a CDR3 having SEQ ID NO: 6.

39 . The method of any one of claims 29 to 38 , wherein the anti-cotinine antibody has a heavy chain and a light chain, the heavy chain comprising a heavy chain variable region (VH) having SEQ ID NO: 7, and the light chain comprising a light chain variable region (VL) having SEQ ID NO: 8.

40 . The method of any one of claims 29 to 39 , wherein the anti-cotinine antibody is of IgG1 isotype comprising a substitution in an Fc region to increase ADCC activity.

41 . The method of claim 40 , wherein the substitution in the Fc region is S239D/I332E, wherein residue numbering is according to the EU Index.

42 . The method of any one of claims 29 to 41 , wherein the anti-cotinine antibody has a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10.

43 . A combination comprising the compound of any one of claims 1 to 28 and an anti-cotinine antibody, or antigen-binding fragment thereof.

44 . The combination of claim 43 , wherein the anti-cotinine antibody has a heavy chain and a light chain, the heavy chain comprising a CDR1 having SEQ ID NO: 1, a CDR2 having SEQ ID NO: 2, and a CDR3 having SEQ ID NO: 3, and the light chain comprising a CDR1 having SEQ ID NO: 4, a CDR2 having SEQ ID NO: 5, and a CDR3 having SEQ ID NO: 6.

45 . The combination of claim 43 or 44 , wherein the anti-cotinine antibody has a heavy chain and a light chain, the heavy chain comprising a heavy chain variable region (VH) having SEQ ID NO: 7, and the light chain comprising a light chain variable region (VL) having SEQ ID NO: 8.

46 . The combination of any one of claims 43 to 45 , wherein the anti-cotinine antibody is of IgG1 isotype comprising a substitution in an Fc region to increase ADCC activity.

47 . The combination of any one of claims 43 to 46 , wherein the substitution in the Fc region is S239D/I332E, wherein residue numbering is according to the EU Index.

48 . The combination of any one of claims 43 to 47 , wherein the anti-cotinine antibody has a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10.