# US 11,028,088 B2 · Modulators of BTK proteolysis and methods of use

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- Number: US 11,028,088 B2
- Document ID: US11028088B2
- Status: Granted
- Kind: B2
- Application number: 16/297,282
- Filed: 2019-03-08
- Published: 2019-09-12
- Granted: 2021-06-08
- Earliest claimed: 2018-03-10
- Assignees: Yale University
- Applicants: Yale University
- Inventors: Craig M. Crews; Saul Jaime-Figueroa; Momar Toure
- Web page: https://patentgrep.com/patent/US11028088B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/14: Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
- A61K 47/545: {Heterocyclic compounds (A61K47/558 takes precedence)}
- A61K 47/55: the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- C07D 401/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present disclosure relates to bifunctional compounds, which find utility as modulators of Burton's Tyrosine Kinase (BTK). In particular, the present disclosure is directed to bifunctional compounds. One end of a bifunctional compound includes a Von Hippel-Lindau, Cereblon, Inhibitors of Apotosis Proteins, or Mouse Double-Minute Homolog 2 ligand that binds to the respective E3 ubiquitin ligase. The other end of a bifunctional compound includes a moiety that binds a target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. Diseases or disorders that result from aggregation, accumulation, and/or overactivation of the target protein can be treated or prevented with compounds and compositions of the present disclosure.

## Claims

### Claim 1

A compound, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, or prodrug thereof, having the structure:
ULM-L-PTM,
wherein:
the ULM is an E3 ubiquitin ligase binding moiety that binds an E3 ubiquitin ligase;
the PTM is a Bruton's Tyrosine Kinase (BTK) targeting moiety having the structure:
wherein:
at each occurrence XPTM is independently N or optionally substituted CH;
RPTM1 is independently NRPTMP9PTM10, H, optionally substituted C3-C6 cycloalkyl,
optionally substituted C3-C6 heteroalkyl, optionally substituted aryl, optionally substituted heteroaryl,
RPTM9 and RPTM10 are each independently H, —(C═O)—RPTM9′, or optionally substituted C1-C6 alkyl;
RPTM9′ is optionally substituted linear or branched alkyl, or optionally substituted alkene;
at each occurrence RPTM2 is independently H, —O—RPTM3, optionally substituted linear or branched alkyl;
at each occurrence RPTM3 is independently an optionally substituted aryl or optionally substituted heteroaryl; and
the indicates a site of attachment of at least one of a linker, ULM, ULM′ or a combination thereof; and
the L is a bond or a linker connecting the ULM and the PTM.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the ULM is selected from the group consisting of an IAP E3 ubiquitin ligase binding moiety (ILM), a cereblon E3 ubiquitin ligase binding moiety (CLM), a Von Hippel-Lindau E3 ubiquitin ligase binding moiety (VLM), a mouse double minute 2 homologue (MDM2) E3 ubiquitin ligase binding moiety (MLM), and combinations thereof.

### Claim 3 (depends on 1)

The compound of claim 1, wherein the PTM has the structure:

### Claim 4 (depends on 1)

The compound of claim 1, wherein the ULM is a Von Hippel-Lindau (VHL) ligase-binding moiety (VLM) with the structure:
wherein:
at each occurrence X1, X2 are each independently selected from the group consisting of a bond, O, NRY3, CRY3RY4, C═O, C═S, SO, and SO2;
RY3, RY4 are each independently selected from the group consisting of H, linear or branched C1-6 alkyl optionally substituted by 1 or more halogen, and C1-6 alkoxyl optionally substituted by 0-3 RP groups;
at each occurrence RP is 0, 1, 2, or 3 groups independently selected from the group consisting of H, halogen, —OH, C1-3 alkyl, and C═O;
at each occurrence W3 is independently selected from the group of an optionally substituted T, an optionally substituted -T-N(R1aR1b)X3, an optionally substituted -T-N(R1aR1b), an optionally substituted -T-Aryl, an optionally substituted -T-Heteroaryl, an optionally substituted -T-Heterocycle, an optionally substituted —NR1-T-Aryl, an optionally substituted —NR1-T-Heteroaryl or an optionally substituted —NR1-T-Heterocycle;
at each occurrence X3 is C(═O), R1, R1a, or R1b;
each of R1, R1a, R1b is independently selected from the group consisting of H, linear or branched C1-C6 alkyl group optionally substituted by 1 or more halogen or —OH groups, RY3C(═O), RY3C═S, RY3SO, RY3SO2, N(RY3RY4)C(═O), N(RY3RY4)C(═S), N(RY3RY4)SO, and N(RY3RY4)SO2;
T is selected from the group of an optionally substituted alkyl, —(CH2)n— group, wherein:
each one of the methylene groups in T is optionally substituted with one or two substituents selected from the group of halogen, methyl, optionally substituted alkoxy, a linear or branched C1-C6 alkyl group optionally substituted by 1 or more halogen, C(═O)NR1R1a, NR1R1a in which R1 and R1a are optionally joined to form substituted heterocycle, —OH, or an optionally substituted amino acid; and
at each occurrence n is independently a whole number from 0 to 6,
at each occurrence W4 is independently
at each occurrence R14a, R14b, are each independently selected from the group consisting of H, haloalkyl, and optionally substituted alkyl;
at each occurrence W5 is independently selected from the group consisting of a phenyl and a 5-10 membered heteroaryl,
at each occurrence R15 is independently selected from the group consisting of H, halogen, CN, OH, NO2, N R14aR14b, OR14a, C(═O)NR14aR14b, NR14aC(═O)R14b, SO2NR14aR14b, NR14a SO2R14b, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted cycloheteroalkyl; and
wherein the dashed line indicates the site of attachment of at least one PTM, another ULM (ULM′) or a chemical linker moiety coupling at least one PTM or a ULM′ or both to ULM.

### Claim 5 (depends on 1)

The compound of claim 1, wherein the ULM is a Von Hippel-Lindau (VHL) ligase-binding moiety (VLM) with a structure represented by:
wherein:
at each occurrence W3 is selected from the group consisting of an optionally substituted aryl, optionally substituted heteroaryl, and
at each occurrence R9 and R10 are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl, or R9, R10, and the carbon atom to which they are attached form an optionally substituted cycloalkyl;
at each occurrence R11 is independently selected from the group consisting of an optionally substituted heterocyclic, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aryl,
at each occurrence R12 is independently selected from the group of H or optionally substituted alkyl;
at each occurrence R13 is independently selected from the group of H, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted (cycloalkyl)alkylcarbonyl, optionally substituted aralkylcarbonyl, optionally substituted arylcarbonyl, optionally substituted (heterocyclyl)carbonyl, or optionally substituted aralkyl;
at each occurrence R14a, R14b, are each independently selected from the group of H, haloalkyl, or optionally substituted alkyl;
at each occurrence W5 is selected from the group of a phenyl or a 5-10 membered heteroaryl,
at each occurrence R15 is independently selected from the group of H, halogen, CN, OH, NO2, N R14aR14b, OR14a, CONR14aR14b, NR14aCOR14b, SO2NR14aR14b, NR14a SO2R14b, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl;
at each occurrence R16 is independently selected from the group of halogen, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy;
at each occurrence o is independently 0, 1, 2, 3, or 4;
at each occurrence R18 is independently selected from the group of halogen, optionally substituted alkoxy, cyano, optionally substituted alkyl, haloalkyl, haloalkoxy or a linker; and
at each occurrence p is independently 0, 1, 2, 3, or 4, and wherein the dashed line indicates the site of attachment of at least one PTM, another ULM (ULM′) or a chemical linker moiety coupling at least one PTM or a ULM′ or both to ULM.

### Claim 6 (depends on 1)

The compound of claim 1, wherein the ULM has a chemical structure selected from the group consisting of:
wherein:
at each occurrence R1 is independently H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl;
at each occurrence R14a is independently H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl;
at each occurrence R15 is independently selected from the group consisting of H, halogen, CN, OH, NO2, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted cycloalkyl, and optionally substituted cycloheteroalkyl;
X is C or C(═O)
at each occurrence R3 is absent or an optionally substituted 5 or 6 membered heteroaryl; and
wherein the dashed line indicates the site of attachment of at least one PTM, another ULM (ULM′) or a chemical linker moiety coupling at least one PTM or a ULM′ or both to the ULM.

### Claim 7 (depends on 1)

The compound of claim 1, wherein the ULM comprises a group according to the chemical structure:
wherein:
at each occurrence R1 is independently an optionally substituted C1-C6 alkyl group, an optionally substituted —(CH2)nOH, an optionally substituted —(CH2)nSH, an optionally substituted (CH2)n—O—(C1-C6)alkyl group, an optionally substituted (CH2)n—WCOCW—(C0-C6)alkyl group containing an epoxide moiety WCOCW, wherein
each W is independently H or a C1-C3 alkyl group, an optionally substituted —(CH2)nCOOH, an optionally substituted —(CH2)nC(═O)—(C1-C6 alkyl), an optionally substituted —(CH2)nNHC(═O)—R1, an optionally substituted —(CH2)nC(═O)—NR1R2, an optionally substituted —(CH2)nOC(═O)—NR1R?, —(CH2O)nH, an optionally substituted —(CH2)nOC(═O)—(C1-C6 alkyl), an optionally substituted —(CH2)nC(═O)—O—(C1-C6 alkyl), an optionally substituted —(CH2O)nCOOH, an optionally substituted —(OCH2)nO—(C1-C6 alkyl), an optionally substituted —(CH2O)nC(═O)—(C1-C6 alkyl), an optionally substituted —(OCH2)nNHC(═O)—R1, an optionally substituted —(CH2O)nC(═O)—NR1R2, —(CH2CH2O)nH, an optionally substituted —(CH2CH2O)nCOOH, an optionally substituted —(OCH2CH2)nO—(C1-C6 alkyl), an optionally substituted —(CH2CH2O)nC(═O)—(C1-C6 alkyl), an optionally substituted —(OCH2CH2)nNHC(═O)—R1, an optionally substituted —(CH2CH2O)nC(═O)—NR1R2,an optionally substituted —SO2RS, an optionally substituted S(═O)RS, NO2, CN or halogen;
at each occurrence R1 and R2 are each independently H or a C1-C6 alkyl group which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups;
at each occurrence RS is a C1-C6 alkyl group, an optionally substituted aryl, heteroaryl or heterocycle group or a —(CH2)mNR1R2 group;
X and X′ are each independently C═O, C═S, —S(═O), S(═O)2;
at each occurrence R2 is independently an optionally substituted —(CH2)n—(C═O)u(NR1)v(SO2)walkyl group, an optionally substituted —(CH2)n—(C═O)u(NR1)v(SO2)wNR1NR2N group, an optionally substituted —(CH2)n—(C═O)u(NR1)v(SO2)w-Aryl, an optionally substituted —(CH2)n—(C═O)u(NR1)v(SO2)w-Heteroaryl, an optionally substituted —(CH2)n—(C═O)vNR1(SO2)w-Heterocycle, an optionally substituted —NR1—(CH2)n—C(═O)u(NR1)v(SO2)w-alkyl, an optionally substituted —NR1—(CH2)n—C(═O)u(NR1)v(SO2)w—NR1NR2N, an optionally substituted —NR1—(CH2)n—C(═O)u(NR1)v(SO2)w—NR1C(═O)R1N, an optionally substituted —NR1—(CH2)n—(C═O)u(NR1)v(SO2)w-Aryl, an optionally substituted —NR1—(CH2)n—(C═O)u(NR1)v(SO2)w-Heteroaryl or an optionally substituted —NR1—(CH2)n—(C═O)vNR1(SO2)w-Heterocycle, an optionally substituted —XR2′-alkyl group; an optionally substituted —XR2′— Aryl group; an optionally substituted —XR2′— Heteroaryl group; an optionally substituted —XR2′— Heterocycle group;
at each occurrence R3′ is independently an optionally substituted alkyl, an optionally substituted —(CH2)n—(O)u(NR1)v(SO2)w-alkyl, an optionally substituted —(CH2)n—C(═O)u(NR1)v(SO2)w—NR1NR2N, an optionally substituted —(CH2)n—C(═O)u(NR1)v(SO2)w—NR1C(═O)R1N, an optionally substituted —(CH2)n—C(═O)u(NR1)v(SO2)w—C(═O)NR1R2, an optionally substituted —(CH2)n—C(═O)u(NR1)v(SO2)w-Aryl, an optionally substituted —(CH2)n—C(═O)u(NR1)v(SO2)w-Heteroaryl, an optionally substituted —(CH2)n—C(═O)u(NR1)v(SO2)w-Heterocycle, an optionally substituted —NR1—(CH2)n—C(═O)u(NR1)v(SO2)w-alkyl, an optionally substituted —NR1—(CH2)n—C(═O)u(NR1)v(SO2)w— NR1NR2N, an optionally substituted —NR1—(CH2)n—C(═O)u(NR1)v(SO2)w—NR1C(═O)R1N, an optionally substituted —NR1—(CH2)n—C(═O)u(NR1)v(SO2)w-Aryl, an optionally substituted —NR1—(CH2)n—C(═O)u(NR1)v(SO2)w-Heteroaryl, an optionally substituted —NR1—(CH2)n—C(═O)u(NR1)v(SO2)w-Heterocycle, an optionally substituted —O—(CH2)n—(C═O)u(NR1)v(SO2)w-alkyl, an optionally substituted —O—(CH2)n—(C═O)u(NR1)v(SO2)w—NR1NR2N, an optionally substituted —O—(CH2)n—(C═O)u(NR1)v(SO2)w—NR1C(═O)R1N, an optionally substituted —O—(CH2)n—(C═O)u(NR1)v(SO2)w-Aryl, an optionally substituted —O—(CH2)n—(C═O)u(NR1)v(SO2)w-Heteroaryl or an optionally substituted —O—(CH2)n—(C═O)u(NR1)v(SO2)w-Heterocycle; —(CH2)n—(V)n′—(CH2)n—(V)n′-alkyl group, an optionally substituted —(CH2)n—(V)n′—(CH2)n—(V)n′-Aryl group, an optionally substituted —(CH2)n—(V)n′—(CH2)n′—(V)n′-Heteroaryl group, an optionally substituted —(CH2)n—(V)n′—(CH2)n—(V)n′-Heterocycle group, an optionally substituted —(CH2)n—N(R1′)(C═O)m′—(V)n′-alkyl group, an optionally substituted —(CH2)n—N(R1′)(C═O)m′—(V)n-Aryl group, an optionally substituted —(CH2)n—N(R1′)(C═O)m′—(V)n′-Heteroaryl group, an optionally substituted —(CH2)n—N(R1′)(C═O)m′—(V)n′-Heterocycle group, an optionally substituted —XR3′— alkyl group; an optionally substituted —XR3′— Aryl group; an optionally substituted —XR3′— Heteroaryl group; an optionally substituted —XR3′— Heterocycle group;
at each occurrence R1N and R2N are each independently H, C1-C6 alkyl which is optionally substituted with one or two hydroxyl groups and up to three halogen groups or an optionally substituted —(CH2)n-Aryl, —(CH2)n—Heteroaryl or —(CH2)n—Heterocycle group;
at each occurrence V is O, S or MU;
at each occurrence R1 and R1′ are each independently H or a C1-C3 alkyl group;
at each occurrence XR2′ and XR3′ are each independently an optionally substituted —CH2)n—, —CH2)n—CH(Xv)═CH(Xv)— (cis or trans), —CH2)n—CH≡CH—, —(CH2CH2O)n— or a C3-C6 cycloalkyl group, wherein
at each occurrence Xv is independently H, a halogen, or an optionally substituted C1-C3 alkyl group;
at each occurrence m is independently 0, 1, 2, 3, 4, 5, 6;
at each occurrence m′ is independently 0 or 1;
at each occurrence n is independently 0, 1, 2, 3, 4, 5, 6;
at each occurrence n′ is independently 0 or 1;
at each occurrence u of is independently 0 or 1;
at each occurrence v is independently 0 or 1;
at each occurrence w is independently 0 or 1; and
at each occurrence R1′, R2′, R3′, X and X′ is independently optionally modified to be covalently bonded to the PTM group through a linker group when PTM is not ULM′, or when PTM is ULM′, any one or more of R1′, R2′, R3′, X and X′ of each of ULM and ULM′ are optionally modified to be covalently bonded to each other directly or through a linker group.

### Claim 8 (depends on 1)

The compound of claim 1, wherein the ULM is a cereblon E3 ligase-binding moiety (CLM) selected from the group consisting of a thalidomide, lenalidomide, and pomalidomide.

### Claim 9 (depends on 2)

The compound of claim 2, wherein the CLM has a structure selected from:
wherein:
at each occurrence W is selected from the group consisting of CH2, CHR, C(═O), SO2, NH, and N-alkyl;
at each occurrence X is independently selected from the group consisting of O, S, and H2;
at each occurrence Y is selected from the group consisting of CH2, —C═CR′, NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and S;
at each occurrence Z is selected from the group consisting of O, S, and H2;
at each occurrence G and G′ are independently selected from the group consisting of H, optionally substituted linear or branched alkyl, OH, R′OCOOR, R′OCONRR″, CH2-heterocyclyl optionally substituted with R′, and benzyl optionally substituted with R′;
at each occurrence Q1, Q2, Q3, and Q4 represent a carbon atom substituted with a group independently selected from R′, N, or N-oxide;
at each occurrence A is independently selected from the group H, optionally substituted linear or branched alkyl, cycloalkyl, Cl, or F;
at each occurrence R is selected from the group consisting of —CONR′R″, —OR′, —NR′R″, —SR′, —SO2R′, —SO2NR′R″, —CR′R″—, —CR′NR′R″—, (—CR′O)nR″, -aryl, -hetaryl, optionally substituted linear or branched alkyl, -cycloalkyl, -heterocyclyl, —P(═O)(OR′)R″, —P(═O)R′R″, —OP(═O)(OR′)R″, —OP(═O)R′R″, —Cl, —F, —Br, —I, —CF3, —CN, -MCSO2MCR″, —NR′CONR′R″, —CONR′COR″, —NR′C(═N—CN)NR′R″, —C(═N—CN)NR′R″, —NR′C(═N—CN)R″, —NR′C(═C—NO2)NR′R″, —SO2NR′COR″, —NO2, —CO2R′, —C(C═N—OR′)R″, —CR′═CR′R″, —C═CR′, —S(C═O)(C═N—R′)R″, —SF5 and —OCF3;
at each occurrence R′ and R″ are independently selected from the group consisting of a bond, H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, —C(═O)R, and heterocyclyl, each of which is optionally substituted;
at each occurrence represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; and
at each occurrence Rn is from 1 to 4 groups selected from H, OH, C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl, amine, amide, or carboxy,
wherein at each occurrence n is independently an integer from 1-10, and wherein when n is 1, Rn is modified to be covalently joined to the linker group (L), and
when n is 2, 3, or 4, then one Rn is modified to be covalently joined to the linker group (L), and any other Rn is optionally modified to be covalently joined to a PTM, a CLM, a second CLM having the same chemical structure as the CLM, a CLM′, a second linker, or any combination thereof.

### Claim 10 (depends on 2)

The compound of claim 2, wherein the CLM has a structure selected from:
wherein:
at each occurrence W is independently selected from CH2, CHR, C═O, SO2, NH, and N-alkyl;
at each occurrence Q1, Q2, Q3, Q4, Q5 are each independently C or N substituted with a group independently selected from R′, N or N-oxide;
at each occurrence R1 is independently selected from absent, H, OH, CN, C1-C3 alkyl, C═O;
at each occurrence R2 is independently selected from the group absent, H, OH, CN, C1-C3 alkyl, CHF2, CF3, CHO, C(═O)NH2;
at each occurrence R3 is independently selected from H, alkyl, alkoxy, substituted alkoxy;
at each occurrence R4 is independently selected from H, alkyl, substituted alkyl;
at each occurrence R5 and R6 are each independently H, halogen, C(═O)R′, CN, OH, CF3;
at each occurrence X is independently C, CH, C═O, or N;
at each occurrence X1 is independently C═O, N, CH, or CH2;
at each occurrence R′ is independently selected from H, halogen, amine, alkyl, substituted alkyl, alkoxy, substituted alkoxy, NR2R3, C(═O)OR2, or optionally substituted phenyl;
at each occurrence n is independently 0-4;
at each occurrence is a single or double bond; and
the CLM is covalently joined to a PTM, a chemical linker group (L), a ULM, CLM, CLM′, or combinations thereof.

### Claim 11 (depends on 1)

The compound of claim 1, wherein the ULM is an MDM2 binding moiety (MLM) selected from the group consisting of a substituted imidazoline, a substituted spiro-indolinone, a substituted pyrrolidine, a substituted piperidinone, a substituted morpholinone, a substituted pyrrolopyrimidine, a substituted imidazolopyridine, a substituted thiazoloimidazoline, a substituted pyrrolopyrrolidinone, and a substituted isoquinolinone.

### Claim 12 (depends on 1)

The compound of claim 1, wherein the ULM is a IAP E3 ubiquitin ligase binding moiety (ILM) comprising alanine (A), valine (V), proline (P), or isoleucine (I), combinations thereof, or their unnatural mimetics.

### Claim 13 (depends on 1)

The compound of claim 1, wherein the ULM is a IAP E3 ubiquitin ligase binding moiety (ILM) comprising an AVPI tetrapeptide fragment or derivative thereof.

### Claim 14 (depends on 1)

The compound of claim 1, wherein the linker (L) comprises a chemical structural unit represented by the formula:
-(AL)q-,
wherein:
-(AL)q-is a group which is connected to at least one of ULM, PTM, or both;
q is an integer greater than or equal to 1;
each AL is independently selected from the group consisting of, a bond, CRL1RL2, O, S, S(═O), SO2, NRL3, SO2NRL3, SONRL3, CONRL3, NRL3CONRL4, NRL3SO2NRL4, C(═O), CRL1═CRL2, C═C, SiRL1RL2, P(═O)RL1, P(═O)OR11, NRL3C(═NCN)NRL4, NRL3C(═NCN), NRL3C(═CNO2)NRL4, C3-11cycloalkyl optionally substituted with 0-6 RL1 or RL2 groups, C3-11heterocyclyl optionally substituted with 0-6 RL1 or RL2 groups, aryl optionally substituted with 0-6 RL1 or RL2 groups, heteroaryl optionally substituted with 0-6 RL1 or RL2 groups, where RL1 or RL2, each independently are optionally linked to other groups to form cycloalkyl or heterocyclyl moiety, optionally substituted with 0-4 RL5 groups; and
RL1, RL2, RL3, RL4 and RL5 are, each independently, H, halogen, C1-8alkyl, OC1-8alkyl, SC1-8alkyl, NHC1-8alkyl, N(C1-8alkyl)2, C3-11cycloalkyl, aryl, heteroaryl, C3-11heterocyclyl, OC1-8cycloalkyl, SC1-8cycloalkyl, NHC1-8cycloalkyl, N(C1-8cycloalkyl)2, N(C1-8cycloalkyl)(C1-8alkyl), OH, NH2, SH, SO2C1-8alkyl, P(═O)(OC1-8alkyl)(C1-8alkyl), P(═O)(OC1-8alkyl)2, C≡C—C1-8alkyl, C═CH, CH≡CH(C1-8alkyl), C(C1-8alkyl)═CH(C1-8alkyl), C(C1-8alkyl)═C(C1-8alkyl)2, Si(OH)3, Si(C1-8alkyl)3, Si(OH)(C1-8alkyl)2, COC1-8alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC1-8alkyl, SO2N(C1-8alkyl)2, SONHC1-8alkyl, SON(C1-8alkyl)2, CONHC1-8alkyl, CON(C1-8alkyl)2, N(C1-8alkyl)CONH(C1-8alkyl), N(C1-8alkyl)CON(C1-8alkyl)2, NHCONH(C1-8 alkyl), NHCON(C1-8alkyl)2, NHCONH2, N(C1-8alkyl)SO2NH(C1-8alkyl), N(C1-8alkyl) SO2N(C1-8alkyl)2, NH SO2NH(C1-8alkyl), NH SO2N(C1-8alkyl)2, NH SO2NH2.

### Claim 15 (depends on 1)

The compound of claim 1, wherein the linker (L) is selected from the group consisting of:
—N(R)—(CH2)m—O(CH2)n—O(CH2)o—O(CH2)p—O(CH2)q—O(CH2)r—OCH2—, —O—(CH2)m—O(CH2)n—O(CH2)o—O(CH2)p—O(CH2)q—O(CH2)r—OCH2—, —O—(CH2)m—O(CH2)n—O(CH2)o—O(CH2)p—O(CH2)q—O(CH2)r—O—, —N(R)—(CH2)m—O(CH2)n—O(CH2)o—O(CH2)p—O(CH2)q—O(CH2)r—O—, —(CH2)m—O(CH2)n—O(CH2)o—O(CH2)p—O(CH2)q—O(CH2)r—O—, —(CH2)m—O(CH2)n—O(CH2)o—O(CH2)p—O(CH2)q—O(CH2)r—OCH2—,
wherein each m, n, o, p, q, and r, is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, with the proviso that when m, n, o, p, q, or r is zero, there is no N-0 or C1-C6 bond, at each occurrence R is independently selected from the group consisting of H, methyl, and ethyl, and at each occurrence X is H or F.

### Claim 16 (depends on 1)

The compound of claim 1, wherein the linker (L) is selected from the group consisting of:
wherein at each occurrence m and n is independently selected from 0, 1, 2, 3, 4, 5, or 6.

### Claim 17 (depends on 1)

The compound of claim 1, wherein the linker (L) is selected from the group consisting of:
wherein at each occurrence m, n, o, p, q, and r is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

### Claim 18 (depends on 1)

The compound of claim 1, wherein the linker L is selected from the group consisting of:

### Claim 19 (depends on 1)

The compound of claim 1, wherein the linker (L) is a polyethylenoxy group optionally substituted with aryl or phenyl comprising from 1 to 10 ethylene glycol units.

### Claim 20 (depends on 1)

The compound of claim 1, wherein the linker (L) has the following chemical structure:
wherein:
at each occurrence WL1 and WL2 are each independently absent, a 4-8 membered ring with 0-4 heteroatoms, optionally substituted with RQ, each RQ is independently a H, halogen, OH, CN, CF3, C1-C6alkyl, C1-C6 alkoxy, or 2 RQ groups taken together with the atom they are attached to form a 4-8 membered ring system containing 0-4 heteroatoms;
at each occurrence YL1 is each independently a bond, C1-C6 alkyl and optionally one or more C atoms are replaced with O; or C1-C6 alkoxy;
at each occurrence n is independently 0-10; and
at each occurrence a dashed line indicates the attachment point to the PTM or ULM moieties.

### Claim 21 (depends on 1)

The compound of claim 1, wherein the linker (L) has the structure:
wherein:
at each occurrence WL1 and WL2 are each independently absent, aryl, heteroaryl, cyclic, heterocyclic, C1-6 alkyl and optionally one or more C atoms are replaced with O, C1-6 alkene and optionally one or more C atoms are replaced with O, C1-6 alkyne and optionally one or more C atoms are replaced with O, bicyclic, biaryl, biheteroaryl, or biheterocyclic, each optionally substituted with RQ, each RQ is independently a H, halogen, OH, CN, CF3, hydroxyl, nitro, C═CH, C2-6 alkenyl, C2-6 alkynyl, C1-C6 alkyl (linear, branched, optionally substituted), C1-C6 alkoxy (linear, branched, optionally substituted), OC1-3alkyl (optionally substituted by 1 or more —F), OH, NH2, NRY1RY2, CN, or 2 RQ groups taken together with the atom they are attached to, form a 4-8 membered ring system containing 0-4 heteroatoms;
at each occurrence YL1 is independently a bond, NRYL1, O, S, NRYL2, CRYLIRYL2, C═O, C═S, SO, SO2, C1-C6 alkyl (linear, branched, optionally substituted) and optionally one or more C atoms are replaced with O; C1-C6 alkoxy (linear, branched, optionally substituted);
at each occurrence QL is independently a 3-6 membered alicyclic or aromatic ring with 0-4 heteroatoms, optionally bridged, optionally substituted with 0-6 RQ, each RQ is independently H, C1-6 alkyl (linear, branched, optionally substituted by 1 or more halogen, C1-6 alkoxyl), or 2 RQ groups taken together with the atom they are attached to, form a 3-8 membered ring system containing 0-2 heteroatoms);
at each occurrence RYL1, RYL2 are each independently H, OH, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxyl, or R1 and R2 together with the atom they are attached to form a 3-8 membered ring system containing 0-2 heteroatoms;
at each occurrence n is independently 0-10; and
at each occurrence a dashed line indicates the attachment point to the PTM or ULM moieties.

### Claim 22 (depends on 1)

The compound of claim 1, wherein the linker (L) is selected from the group consisting of:

### Claim 23 (depends on 1)

The compound claim 1, wherein the linker is selected from:
wherein at each occurrence m, n, o, p, and q are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

### Claim 24 (depends on 1)

The compound of claim 1, wherein:
the PTM is
the linker (L) is selected from the group consisting of L-1, L-2, L-3, L-4, L-5, L-6, L-7, L-8, L-9, L-10, L-11, L-12, L-13, L-14, L-15, L-16, L-17, L-18, L-19, L-20, L-21, and L-22; and
the ULM is selected from the group consisting of ULM-1, ULM-2, ULM-3, ULM-4, and ULM-5; or combinations thereof.

### Claim 25 (depends on 1)

The compound of claim 1, wherein the linker (L) is selected from the group consisting of L-1, L-2, L-3, L-4, L-5, L-6, L-7, L-8, L-9, L-10, L-11, L-12, L-13, L-14, L-15, L-16, L-17, L-18, L-19, L-20, L-21, and L-22.

### Claim 26 (depends on 1)

The compound of claim 1, wherein the ULM is selected from the group consisting of ULM-1, ULM-2, ULM-3, ULM-4, and ULM-5.

### Claim 27

A compound selected from the group consisting of:

### Claim 28 (depends on 1)

A composition comprising a therapeutically effective amount of a compound of claim 1, and a pharmaceutically acceptable carrier.

### Claim 29 (depends on 28)

The composition of claim 28, wherein the composition further comprises at least one of additional bioactive agent.

### Claim 30 (depends on 29)

The composition of claim 29, wherein the additional bioactive agent is an anti-cancer agent.

### Claim 31 (depends on 1)

A composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound of claim 1 for treating a disease or disorder in a subject, the method comprising administering the composition to a subject in need thereof, wherein the compound is effective in treating or ameliorating at least one symptom of the disease or disorder.

### Claim 32 (depends on 31)

The composition of claim 31, wherein the disease or disorder is associated with at least one of accumulation, aggregation, overactivation, or combinations thereof, of BTKs.

### Claim 33 (depends on 31)

The composition of claim 31, wherein the disease or disorder is cancer that is associated with the accumulation, aggregation, or overactivation of BTKs.

### Claim 34 (depends on 32)

The composition of claim 32, wherein the disease or disorder is leukemia, pancreatic cancer, colon cancer, colorectal cancer, lung cancer, non-small cell lung cancer, biliary tract malignancies, endometrial cancer, cervical cancer, bladder cancer, liver cancer, myeloid leukemia, and breast cancer.

### Claim 35 (depends on 31)

The composition of claim 31, wherein the disease or disorder is chronic lymphocytic leukemia.