# US 2019/0315752 A1 · Bicyclic urea kinase inhibitors and uses thereof

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- Number: US 2019/0315752 A1
- Document ID: US20190315752A1
- Status: Published application
- Kind: A1
- Application number: 16/315,438
- Filed: 2017-07-05
- Published: 2019-10-17
- Earliest claimed: 2016-07-05
- Assignees: The Broad Institute, Inc.; Dana-Farber Cancer Institute, Inc.; The General Hospital Corporation
- Applicants: The Broad Institute, Inc.; Dana-Farber Cancer Institute, Inc.; The General Hospital Corporation
- Inventors: Nathanael S. GRAY; Yanke LIANG; Hwan Geun CHOI; Thomas SUNDBERG; Alykhan SHAMJI; Ramnik XAVIER; David E. FISHER; Nisma MUJAHID
- Web page: https://patentgrep.com/patent/US20190315752A1

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 19/00: Drugs for skeletal disorders
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

The present disclosure provides compounds of Formula (I), (II), and (III). The provided compounds are able to bind protein kinases (e.g., SIK) and may be useful in modulating (e.g., inhibiting) the activity of a protein kinase (e.g., SIK, (e.g., SIK1, SIK2, or SIK3)) in a subject or cell. The provided compounds may be useful in treating or preventing a disease (e.g., proliferative disease, musculoskeletal disease, genetic disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder) in a subject in need thereof. Also provided are pharmaceutical compositions, kits, methods, and uses that include or involve a compound described herein.

## Claims

### Claim 1

A compound of Formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
RA is substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl, provided that the substituted or unsubstituted heterocyclyl is not substituted or unsubstituted 3-pyrrolidinyl;
each instance of RA1 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —ORa, —N(Rb)2, —SRa, —CN, —SCN, —C(═NRb)Ra, —C(═NRb)ORa, —C(═NRb)N(Rb)2, —C(═O)Ra, —C(═O)ORa, —C(═O)N(Rb)2, —NO2, —NRbC(═O)Ra, —NRbC(═O)ORa, —NRbC(═O)N(Rb)2, —OC(═O)Ra, —OC(═O)ORa, or —OC(═O)N(Rb)2;
each instance of Ra is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom;
each instance of Rb is independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group, or optionally two instances of Rb are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
k is 0, 1, 2, 3, or 4;
each instance of RB is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —ORa, —N(Rb)2, —SRa, —CN, —SCN, —C(═NRb)Ra, —C(═NRb)ORa, —C(═NRb)N(Rb)2, —C(═O)Ra, —C(═O)ORa, —C(═O)N(Rb)2, —NO2, —NRbC(═O)Ra, —NRbC(═O)ORa, —NRbC(═O)N(Rb)2, —OC(═O)Ra, —OC(═O)ORa, or —OC(═O)N(Rb)2;
m is 0, 1, 2, 3, 4, or 5;
RC is hydrogen, halogen, or substituted or unsubstituted C1-6 alkyl;
RD is hydrogen, halogen, or substituted or unsubstituted C1-6 alkyl;
RE is hydrogen, halogen, or substituted or unsubstituted C1-6 alkyl;
RF is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group;
Ring A is substituted or unsubstituted phenyl; substituted or unsubstituted, polycyclic aryl; substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl; or substituted or unsubstituted, polycyclic heteroaryl;
each instance of RG is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —ORa, —N(Rb)2, —SRa, —CN, —SCN, —C(═NRb)Ra, —C(═NRb)ORa, —C(═NRb)N(Rb)2, —C(═O)Ra, —C(═O)ORa, —C(═O)N(Rb)2, —NO2, —NRbC(═O)Ra, —NRbC(═O)ORa, —NRbC(═O)N(Rb)2, —OC(═O)Ra, —OC(═O)ORa, or —OC(═O)N(Rb)2;
n is 0, 1, 2, 3, or 4, as valency permits;
L is a bond or a substituted or unsubstituted C1-6 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C(═O)—, —O—, —S—, —NRb—, —N═, or ═N—; and
RH is substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted heterocyclyl, —OH, or —N(Rc)2, wherein each instance of Rc is independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group, or optionally two instances of Rc are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.

### Claim 2 (depends on 1)

The compound of claim 1, wherein RA is

### Claim 3 (depends on 1)

The compound of claim 1, wherein RA is

### Claim 4 (depends on 1)

The compound of claim 1, wherein RA is

### Claim 5 (depends on 1)

The compound of claim 1, wherein RA is

### Claim 6 (depends on 1)

The compound of claim 1, wherein RA is substituted or unsubstituted heterocyclyl, provided that the substituted or unsubstituted heterocyclyl is not substituted or unsubstituted 3-pyrrolidinyl.

### Claim 7 (depends on 1)

The compound of claim 1, wherein RA is substituted or unsubstituted tetrahydropyranyl.

### Claim 8 (depends on 1, 2, 3, 4, 5, 6, 7)

The compound of any one of claims 1-7, wherein RB is halogen or methyl.

### Claim 9 (depends on 1, 2, 3, 4, 5, 6, 7, 8)

The compound of any one of claims 1-8, wherein Ring A is phenyl.

### Claim 10 (depends on 1, 2, 3, 4, 5, 6, 7, 8)

The compound of any one of claims 1-8, wherein Ring A is pyrazole or pyridinyl.

### Claim 11 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The compound of any one of claims 1-10, wherein L is a bond.

### Claim 12 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The compound of any one of claims 1-10, wherein L is an unsubstituted C1-3 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —O— or —NRb—.

### Claim 13 (depends on 12)

The compound of claim 12, wherein one chain atom of the hydrocarbon chain is independently replaced with —O—.

### Claim 14 (depends on 13)

The compound of claim 13, wherein L is of the formula:
wherein lA indicates the point of attachment to Ring A, and lR indicates the point of attachment to RH.

### Claim 15 (depends on 12)

The compound of claim 12, wherein L is of the formula:
wherein lA indicates the point of attachment to Ring A, and lR indicates the point of attachment to RH.

### Claim 16 (depends on 12)

The compound of claim 12, wherein L is of the formula:
wherein lA indicates the point of attachment to Ring A, and lR indicates the point of attachment to RH.

### Claim 17 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16)

The compound of any one of claims 1-16, wherein RH is methyl or ethyl.

### Claim 18 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16)

The compound of any one of claims 1-16, wherein RH is substituted or unsubstituted heterocyclyl.

### Claim 19 (depends on 18)

The compound of claim 18, wherein RH is substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl.

### Claim 20 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16)

The compound of any one of claims 1-16, wherein RH is substituted or unsubstituted C1-6 alkyl.

### Claim 21 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16)

The compound of any one of claims 1-16, wherein RH is —OH.

### Claim 22 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16)

The compound of any one of claims 1-16, wherein RH is —N(Rc)2.

### Claim 23 (depends on 22)

The compound of claim 22, wherein each instance of R is substituted or unsubstituted C1-6 alkyl.

### Claim 24 (depends on 22)

The compound of claim 22, wherein each instance of Rc is methyl.

### Claim 25 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24)

The compound of any one of claims 1-24, wherein RC is hydrogen.

### Claim 26 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25)

The compound of any one of claims 1-25, wherein RD is hydrogen.

### Claim 27 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26)

The compound of any one of claims 1-26, wherein RE is hydrogen.

### Claim 28 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27)

The compound of any one of claims 1-27, wherein RE is hydrogen.

### Claim 29 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24)

The compound of any one of claims 1-24, wherein RC, RD, RE, and RF are each hydrogen.

### Claim 30 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29)

The compound of any one of claims 1-29, wherein at least one instance of RG is substituted or unsubstituted C1-3 alkyl.

### Claim 31 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30)

The compound of any one of claims 1-30, wherein at least one instance of RG is halogen.

### Claim 32 (depends on 31)

The compound of claim 31, wherein at least one instance of RG is Br, Cl, or F.

### Claim 33 (depends on 30)

The compound of claim 30, wherein at least one instance of RG is methyl, ethyl, or —CF3.

### Claim 34 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33)

The compound of any one of claims 1-33, wherein at least one instance of RG is —ORa, wherein Ra is substituted or unsubstituted C1-6 alkyl.

### Claim 35 (depends on 34)

The compound of claim 34, wherein at least one instance of RG is —OMe, —OEt, or —O(iPr).

### Claim 36 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35)

The compound of any one of claims 1-35, wherein at least one instance of RG is substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl.

### Claim 37 (depends on 36)

The compound of claim 36, wherein at least one instance of RG is of the formula:

### Claim 38 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37)

The compound of any one of claims 1-37, wherein n is 0, 1, or 2.

### Claim 39 (depends on 1)

The compound of claim 1, wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.

### Claim 40 (depends on 1)

The compound of claim 1, wherein the compound of Formula (I) is not of the formula:
or a pharmaceutically acceptable salt thereof.

### Claim 41

A compound of Formula (II):
or a pharmaceutically acceptable salt thereof,
wherein:
RJ is substituted or unsubstituted carbocyclyl;
each instance of RB is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —ORa, —N(Rb)2, —SRa, —CN, —SCN, —C(═NRb)Ra, —C(═NRb)ORa, —C(═NRb)N(Rb)2, —C(═O)Ra, —C(═O)ORa, —C(═O)N(Rb)2, —NO2, —NRbC(═O)Ra, —NRbC(═O)ORa, —NRbC(═O)N(Rb)2, —OC(═O)Ra, —OC(═O)ORa, or —OC(═O)N(Rb)2;
each instance of Ra is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom;
each instance of Rb is independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group, or optionally two instances of Rb are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
m is 0, 1, 2, 3, 4, or 5;
RC is hydrogen, halogen, or substituted or unsubstituted C1-6 alkyl;
RD is hydrogen, halogen, or substituted or unsubstituted C1-6 alkyl;
RE is hydrogen, halogen, or substituted or unsubstituted C1-6 alkyl;
RF is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group;
Ring A is substituted or unsubstituted phenyl; substituted or unsubstituted, polycyclic aryl; substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl; or substituted or unsubstituted, polycyclic heteroaryl;
each instance of RG is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —ORa, —N(Rb)2, —SRa, —CN, —SCN, —C(═NRb)Ra, —C(═NRb)ORa, —C(═NRb)N(Rb)2, —C(═O)Ra, —C(═O)ORa, —C(═O)N(Rb)2, —NO2, —NRbC(═O)Ra, —NRbC(═O)ORa, —NRbC(═O)N(Rb)2, —OC(═O)Ra, —OC(═O)ORa, or —OC(═O)N(Rb)2;
n is 0, 1, 2, 3, or 4, as valency permits; and
RK is unsubstituted methyl, substituted or unsubstituted heterocyclyl, —ORa, or —N(Rc)2, wherein each instance of Rc is independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group, or optionally two instances of Rc are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.

### Claim 42 (depends on 41)

The compound of claim 41, wherein RJ is substituted or unsubstituted, 4- to 6-membered carbocyclyl.

### Claim 43 (depends on 41)

The compound of claim 41, wherein RJ is substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, or substituted or unsubstituted cyclohexyl.

### Claim 44 (depends on 41, 42, 43)

The compound of any one of claims 41-43, wherein RK is substituted or unsubstituted heterocyclyl.

### Claim 45 (depends on 44)

The compound of claim 44, wherein RK is substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl.

### Claim 46 (depends on 41, 42, 43)

The compound of any one of claims 41-43, wherein RK is —N(Rc)2.

### Claim 47 (depends on 46)

The compound of claim 46, wherein each instance of R is substituted or unsubstituted C1-6 alkyl.

### Claim 48 (depends on 41, 42, 43, 44, 45, 46, 47)

The compound of any one of claims 41-47, wherein at least one instance of RG is —ORa, wherein Ra is substituted or unsubstituted C1-6 alkyl.

### Claim 49 (depends on 48)

The compound of claim 48, wherein at least one instance of RG is —OMe.

### Claim 50 (depends on 41, 42, 43, 44, 45, 46, 47, 48, 49)

The compound of any one of claims 41-49, wherein m is 2.

### Claim 51 (depends on 50)

The compound of claim 50, wherein Ring B is of the formula:

### Claim 52 (depends on 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51)

The compound of any one of claims 41-51, wherein at least one instance of RB is halogen or substituted or unsubstituted C1-6 alkyl.

### Claim 53 (depends on 41, 42, 43, 44, 45, 46, 47, 48, 49)

The compound of any one of claims 41-49, wherein m is 0.

### Claim 54 (depends on 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53)

The compound of any one of claims 41-53, wherein Rc is hydrogen.

### Claim 55 (depends on 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54)

The compound of any one of claims 41-54, wherein RD is hydrogen.

### Claim 56 (depends on 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55)

The compound of any one of claims 41-55, wherein RE is hydrogen.

### Claim 57 (depends on 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56)

The compound of any one of claims 41-56, wherein RF is hydrogen.

### Claim 58 (depends on 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53)

The compound of any one of claims 41-53, wherein RC, RD, RE, and RF are each hydrogen.

### Claim 59 (depends on 41, 42, 43, 44, 45, 46, 47, 50, 51, 52, 53, 54, 55, 56, 57, 58)

The compound of any one of claims 41-47 and 50-58, wherein n is 0.

### Claim 60 (depends on 41)

The compound of claim 41, wherein Ring B is of the formula:
RD, RE, and RF are each hydrogen, RG is —ORa, RJ is substituted or unsubstituted, 4- to 6-membered carbocyclyl, and RK is substituted or unsubstituted piperidinyl, or substituted or unsubstituted piperazinyl.

### Claim 61 (depends on 41)

The compound of claim 41, wherein Ring B is of the formula:
RC, RD, RE, and RF are each hydrogen, n is 0, RJ is substituted or unsubstituted, 4- to 6-membered carbocyclyl, and RK is substituted or unsubstituted piperidinyl, or substituted or unsubstituted piperazinyl.

### Claim 62 (depends on 41)

The compound of claim 41, wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.

### Claim 63

A compound of Formula (III):
or a pharmaceutically acceptable salt thereof,
wherein:
RL is substituted or unsubstituted alkyl;
Ring C is unsubstituted phenyl or of the formula:
each instance of RB1 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —ORa, —N(Rd)2, —SRa, —CN, —SCN, —C(═NRd)Ra, —C(═NRd)ORa, —C(═NRd)N(Rd)2, —C(═O)Ra, —C(═O)ORa, —C(═O)N(Rd)2, —NO2, —NRdC(═O)Ra, —NRdC(═O)ORa, —NRdC(═O)N(Ra)2, —OC(═O)Ra, —OC(═O)ORa, or —OC(═O)N(Rd)2;
each instance of Ra is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom;
each instance of Rd is independently hydrogen, —C(═O)Ra, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group, or optionally two instances of Rd are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
RC is hydrogen, halogen, or substituted or unsubstituted C1-6 alkyl;
RD is hydrogen, halogen, or substituted or unsubstituted C1-6 alkyl;
RE is hydrogen, halogen, or substituted or unsubstituted C1-6 alkyl;
RF is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group;
Ring A is substituted or unsubstituted phenyl; substituted or unsubstituted, polycyclic aryl; substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl; or substituted or unsubstituted, polycyclic heteroaryl;
each instance of RG is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —ORa, —N(Rb)2, —SRa, —CN, —SCN, —C(═NRb)Ra, —C(═NRb)ORa, —C(═NRa)N(Ra)2, —C(═O)Ra, —C(═O)ORa, —C(═O)N(Ra)2, —NO2, —NRbC(═O)Ra, —NRbC(═O)ORa, —NRbC(═O)N(Ra)2, —OC(═O)Ra, —OC(═O)ORa, or —OC(═O)N(Rb)2;
each instance of Rb is independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group, or optionally two instances of Rb are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
n is 0, 1, 2, 3, or 4, as valency permits;
RK is unsubstituted methyl, substituted or unsubstituted heterocyclyl, —ORa, or —N(Rc)2, wherein each instance of Rc is independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group, or optionally two instances of Rc are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; and
RY is substituted phenyl.

### Claim 64 (depends on 63)

The compound of claim 63, wherein RL is substituted or unsubstituted C1-6 alkyl.

### Claim 65 (depends on 63)

The compound of claim 63, wherein RL is Me, Et, iPr, or Pr.

### Claim 66 (depends on 63, 64, 65)

The compound of any one of claims 63-65, wherein Ring C is unsubstituted phenyl.

### Claim 67 (depends on 63, 64, 65)

The compound of any one of claims 63-65, wherein Ring C is of the formula:

### Claim 68 (depends on 63, 64, 65, 66, 67)

The compound of any one of claims 63-67, wherein at least one instance of RB1 is halogen or substituted or unsubstituted C1-6 alkyl, or —N(Rd)2, wherein each instance of Rd is hydrogen or —C(═O)Ra.

### Claim 69 (depends on 67)

The compound of claim 67, wherein Ring C is of the formula:

### Claim 70 (depends on 63, 64, 65, 66, 67, 68, 69)

The compound of any one of claims 63-69, wherein RK is substituted or unsubstituted heterocyclyl.

### Claim 71 (depends on 70)

The compound of claim 70, wherein RK is substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl.

### Claim 72 (depends on 63, 64, 65, 66, 67, 68, 69)

The compound of any one of claims 63-69, wherein RK is —N(Rc)2.

### Claim 73 (depends on 72)

The compound of claim 72, wherein each instance of R is substituted or unsubstituted C1-6 alkyl.

### Claim 74 (depends on 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73)

The compound of any one of claims 63-73, wherein at least one instance of RG is —ORa, wherein Ra is substituted or unsubstituted C1-6 alkyl.

### Claim 75 (depends on 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74)

The compound of any one of claims 63-74, wherein each one of RC and RD is hydrogen.

### Claim 76 (depends on 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74)

The compound of any one of claims 63-74, wherein one of RC and RD is hydrogen, and the other of RC and RD is substituted or unsubstituted C1-6 alkyl.

### Claim 77 (depends on 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76)

The compound of any one of claims 63-76, wherein RE is hydrogen.

### Claim 78 (depends on 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77)

The compound of any one of claims 63-77, wherein RF is hydrogen.

### Claim 79 (depends on 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78)

The compound of any one of claims 63-78, wherein Ring A is substituted or unsubstituted phenyl.

### Claim 80 (depends on 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78)

The compound of any one of claims 63-78, wherein Ring A is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl.

### Claim 81 (depends on 80)

The compound of claim 80, wherein Ring A is substituted or unsubstituted pyridyl or substituted or unsubstituted pyrazolyl.

### Claim 82 (depends on 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81)

The compound of any one of claims 63-81, wherein n is 1.

### Claim 83 (depends on 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81)

The compound of any one of claims 63-81, wherein n is 2.

### Claim 84 (depends on 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83)

The compound of any one of claims 63-83, wherein at least one instance of RG is halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted heterocyclyl, or —ORa.

### Claim 85 (depends on 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 75, 76, 77, 78, 79, 80, 81)

The compound of any one of claims 63-73 and 75-81, wherein n is 0.

### Claim 86 (depends on 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 77, 78, 79, 80, 81, 82, 83, 84, 85)

The compound of any one of claims 63-74 and 77-85, wherein RC is hydrogen.

### Claim 87 (depends on 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86)

The compound of any one of claims 63-74 and 77-86, wherein RD is hydrogen.

### Claim 88 (depends on 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87)

The compound of any one of claims 63-76 and 78-87, wherein RE is hydrogen.

### Claim 89 (depends on 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88)

The compound of any one of claims 63-77 and 79-88, wherein RF is hydrogen.

### Claim 90 (depends on 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 79, 80, 81, 82, 83, 84, 85)

The compound of any one of claims 63-74 and 79-85, wherein RC, RD, RE, and RF are each hydrogen.

### Claim 91 (depends on 63)

The compound of claim 63, wherein Ring C is unsubstituted phenyl, RC, RD, RE, and RF are each hydrogen, n is 0, RL is substituted or unsubstituted C1-6 alkyl, and RK is substituted or unsubstituted piperidinyl, or substituted or unsubstituted piperazinyl.

### Claim 92 (depends on 63)

The compound of claim 63, wherein Ring C is of the formula:
RC, RD, RE, and RF are each hydrogen, RG is —ORa, methyl, or ethyl, RL is substituted or unsubstituted C1-6 alkyl, and RK is substituted or unsubstituted piperidinyl, or substituted or unsubstituted piperazinyl.

### Claim 93 (depends on 63)

The compound of claim 63, wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.

### Claim 94 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93)

A pharmaceutical composition comprising a compound of any one of claims 1-93, and optionally a pharmaceutically acceptable excipient.

### Claim 95 (depends on 94)

The pharmaceutical composition of claim 94 further comprising an additional pharmaceutical agent.

### Claim 96 (depends on 95)

The pharmaceutical composition of claim 95, wherein the additional pharmaceutical agent is a kinase inhibitor.

### Claim 97 (depends on 96)

The pharmaceutical composition of claim 96, wherein the additional pharmaceutical agent is a salt-inducible kinase (SIK) inhibitor.

### Claim 98 (depends on 96)

The pharmaceutical composition of claim 96, wherein the additional pharmaceutical agent is a salt-inducible kinase 2 (SIK2) inhibitor.

### Claim 99 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98)

A method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-93 or a pharmaceutical composition of any one of claims 94-98, wherein the disease is associated with aberrant activity of a protein kinase.

### Claim 100 (depends on 99)

The method of claim 99, wherein the protein kinase is a salt-inducible kinase (SIK).

### Claim 101 (depends on 99)

The method of claim 99, wherein the protein kinase is salt-inducible kinase 2 (SIK2).

### Claim 102 (depends on 99, 100)

The method of any one of claims 99, 100, and 101, wherein the disease is a genetic disease.

### Claim 103 (depends on 99, 100)

The method of any one of claims 99, 100, and 101, wherein the disease is a proliferative disease.

### Claim 104 (depends on 99, 100)

The method of any one of claims 99, 100, and 101, wherein the disease is cancer.

### Claim 105 (depends on 99, 100)

The method of any one of claims 99, 100, and 101, wherein the disease is benign neoplasm.

### Claim 106 (depends on 99, 100)

The method of any one of claims 99, 100, and 101, wherein the disease is pathological angiogenesis.

### Claim 107 (depends on 99, 100)

The method of any one of claims 99, 100, and 101, wherein the disease is an inflammatory disease.

### Claim 108 (depends on 99, 100)

The method of any one of claims 99, 100, and 101, wherein the disease is a musculoskeletal disease.

### Claim 109 (depends on 99, 100)

The method of any one of claims 99, 100, and 101, wherein the disease is an autoimmune disease.

### Claim 110 (depends on 99, 100)

The method of any one of claims 99, 100, and 101, wherein the disease is a hematological disease.

### Claim 111 (depends on 99, 100)

The method of any one of claims 99, 100, and 101, wherein the disease is a neurological disease.

### Claim 112 (depends on 99, 100)

The method of any one of claims 99, 100, and 101, wherein the disease is a painful condition.

### Claim 113 (depends on 99, 100)

The method of any one of claims 99, 100, and 101, wherein the disease is a psychiatric disorder.

### Claim 114 (depends on 99, 100)

The method of any one of claims 99, 100, and 101, wherein the disease is a metabolic disorder.

### Claim 115 (depends on 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114)

The method of any one of claims 99-114, wherein the subject is a human.

### Claim 116 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98)

A kit comprising:
a compound of any one of claims 1-93 or a pharmaceutical composition of any one of claims 94-98; and
instructions for using the compound or pharmaceutical composition.