SIK2 modulators and uses thereof

Abstract

The present invention provides compounds of formula I, compositions thereof, and methods of using the same for the inhibition of SIK2 and the treatment of SIK2-mediated disorders.

Description

SIK2 MODULATORS AND USES THEREOFSEQUENCE LISTING

[0001] This application contains a Sequence Listing which has been submitted in.xml format via EFS and is hereby incorporated by reference. The ST.26 copy, created on December 9, 2025, is named 40102_SeqListing.xml and is 2,216 bytes in size.TECHNICAL FIELD OF THE INVENTION

[0002] The present invention relates to compounds and methods useful for inhibiting salt-inducible kinase 2 (SIK2). The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.BACKGROUND OF THE INVENTION

[0003] A protein kinase is an enzyme that catalyzes the transfer of phosphate groups to proteins or other organic molecules. Consequently, defective control of protein phosphorylation leads to uncontrolled signaling is involved in a number of diseases, including for example, inflammation, allergies, cancer, autoimmune diseases, CNS disorders, and angiogenesis.

[0004] The salt-inducible kinases (SIKs) are Ser / Thr kinases members of the adenosine monophosphate-activated kinase (AMPK) subfamily of kinases and three isoforms have been described, i.e., SIK1, SIK2 (QIK), and SIK3 (QSK). The SIKs play a number of roles in different cell types have been found to phosphorylate a number of substrates including CREB -responsive transcriptional co-activator (CRTC) proteins, and also histone de-acetylase (HDAC) proteins, thereby regulating the transcription of a number of different genes.

[0005] For example, SIK2 is known to play a role in the secretion of high levels of antiinflammatory cytokines such as interleukin- 10 (IL- 10), very low levels of pro-inflammatory cytokines such as TNF-a, and in the regulation of IFNyand IL- 12 signaling, suggesting SIK2 may be an interesting target for inflammatory diseases. See e.g., Darling, et al, Biochem. J. 2017, 474(4):521-537 and Yao, et al., Nat. comm. 2013, 4( 1 ): 1 - 15.

[0006] The lack of selectivity towards salt inducible kinase isoforms, and in particular towards SIK2 may be a possible limitation in the use of such compounds. The aim of the present inventionis to provide new compounds which are potent SIK2 inhibitors, and which also show selectivity over SIK1 and SIK3. There is a need for selective small molecule kinase inhibitors that inhibit SIK2.SUMMARY OF THE INVENTION

[0007] It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as inhibitors of SIK2. In certain embodiments, the invention provides for compounds of the formulae presented herein.

[0008] In one aspect, the disclosure provides a compound of formula I, or a pharmaceutically acceptable salt thereof:Iwherein X, Y, Xi, X2, X3, R1A, R3, Li, L2, L3, L4, L5, a, and Ring C are as described and defined herein.

[0009] Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with modulating SIK2. Such diseases, disorders, or conditions include those described herein. Compounds provided by this invention are also useful for the study of SIK2 kinase in biological and pathological phenomena; the study of intracellular signal transduction pathways occurring in bodily tissues; and the comparative evaluation of new SIK2 inhibitors or other regulators of kinases, signaling pathways, and cytokine levels in vitro or in vivo.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS1. General Description of Certain Embodiments of the Inven tion:

[0010] In certain aspects, the present invention provides a compound of formula I:Ior a pharmaceutically acceptable salt thereof, wherein:X is N or C;Y is N or C, where when one of X and Y is N and the other of X and Y is C;Each = is a single or double bond:Li is selected from a bond, -O-, -S-, -S(O)2-, -NR1-, -C(O)-, -C(O)NR1-, -NR1C(O)-, - NR1C(O)NR1-, and -[C(R1a)(R1b)]1-2-;L2is selected from a bond, a substituted or unsubstituted alkenylene, -O-, -S-, -S(O)2-, -N= S(O)(CH3)-, -S(O)(CH3)=N-, -S(O)2NRJ-, -NR^ O -, -NR1-, -C(O)-, -C(O)NR1-, - NRJC(O)-, -NR1C(O)NR1-, an optionally substituted C3-Ce cycloalkyl, an optionally substituted C3-C6 heterocycloalkyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and-[C(R2a)(R2h)]i-2-;L3 is selected from a bond, a substituted or unsubstituted alkenylene, -O-, -S-, -S(O)2-, -N= S(O)(CH3)-, -S(O)(CH3)=N-, -S(O)2NRJ-, -NR^O -, -NR1-, -C(O)-, -C(O)NRJ-, - NR'CtO)-, -NR1C(O)NR1-, an optionally substituted C3-Ce cycloalkyl, an optionally substituted C3-C6 heterocycloalkyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and-[C(R3a)(R3b)]i-2-;L4 is selected from a bond, a substituted or unsubstituted alkenylene, -O-, -S-, -S(O)2-, -N= S(O)(CH3)-, -S(O)(CH3)=N-, -S(O)2NRJ-, -NR^Ok-, -NR1-, -C(O)-, -C(O)NR1-, - NR1C(O)-, -NR1C(O)NR1-, an optionally substituted C3-C6 cycloalkyl, an optionally substituted C3-Ce heterocycloalkyl (having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), an optionally substituted 5-6 membered monocyclicheteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and-[C(R4a)(R4b)]i-2-;L.5 is selected from a bond, -O-, -S-, -S(O)2-, -NR1-, -C(O)-, -C(O)NR1-, -NR'C(O)-, - NR1C(O)NR1-, and -[C(R5a)(R5b)] 12-;Each R1is independently selected from the group consisting of hydrogen, C1-3 haloalkyl, C1-3 hydroxyalkyl, C0-3 alkyl-Ca-Ce cycloalkyl, C0-3 alkyl-C3-Ce heterocycloalkyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and C1-3 alkyl; wherein C0-3 alkyl-C3-C6 cycloalkyl, C0-3 alkyl-C3-C6 heterocycloalkyl and C1-3 alkyl are substituted with y instances of RB;each RBis independently halogen, C1-3 alkyl, C1-3 hydroxyalkyl, -CN, oxo, -OR, or -NR2; each y is independently 0, 1, 2, or 3;Rla, Rlb, R2a, R2b, R3a, R3b, R4a, R4b, R5a, and R5bare independently selected from the group consisting of hydrogen, halogen, hydroxyl, N(R1)2, C1-3 alkyl, -CN, C1-3 alkoxy, C0-3 alkyl- C3-C6 cycloalkyl, C0-3 alkyl-C3-Ce heterocycloalkyl, and C1-3 hydroxyalkyl, and C1-3 haloalkyl, wherein C0-3 alkyl-C Cr, cycloalkyl, C0-3 alkyl-O-Ce heterocycloalkyl and C1-3 alkyl are substituted with y instances of RB; orRlaand Rlb, R2aand R2b, R3aand R3b, R4aand R4b, or R5aand R5b, and the carbon atom to which they are attached may combine to form:a) a 3-7 membered saturated or partially unsaturated bivalent monocyclic carbocyclylene or 4-7 membered saturated or partially unsaturated bivalent heterocyclylene ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 nitrogen atoms in addition to the 1-4 heteroatoms) - substituted with y instances of RB, orb) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene or heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) - substituted with y instances of RB, orRlaand R2a, Rlaand R3a, R2aand R3a, R2aand R4a, R3aand R4a, R3aand R5a, or R4aand R5a, and the atoms to which they are connected may combine to form:a) a 3-7 membered saturated or partially unsaturated bivalent monocyclic carbocyclylene or a 4-7 membered saturated or partially unsaturated bivalentheterocyclylene ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 nitrogen atoms in addition to the 1-4 heteroatoms) - substituted with y instances of RB, orb) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene or heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) - substituted with y instances of RB;X1 and X2 are each selected from N and CR2provided when Y is N, X1 is CR2;each R2is independently selected from hydrogen, OH, C1-3 alkyl, C1-3 alkoxy, and halogen; X3 is selected from O, S, N, NR7, and CR2, provided when X3 is selected from O, S, and NR7, X and Y areC;R7is hydrogen or C1-3 alkyl;Ring C is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- 12 membered saturated or partially unsaturated bicyclic heterocyclyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R1Ais independently halogen, -CN, oxo, -OR, -SR, -NR2, -SO2R, -SO2NR2, -S(O)R, - S(O)NR2, -C(O)R, -CO2R, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)CO2R, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)R, -N(R)C(NR)NR2, -N(R)NR2, -N(R)SO2NR2, -N(R)SO2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, - P(O)(OR)2, -P(O)R2, CI-C6haloalkyl, C1-3 hydroxyalkyl, C3-C6 halocycloalkyl, Ci-Ce haloalkoxy, or an optionally substituted group selected from Ci 6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;a is 0, 1, 2, or 3;R3is -C(O)-Le, -S(O)2-L6, an optionally substituted C1-6 aliphatic, an optionally substituted C1-6aliphatic substituted with an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from(R6B)bnitrogen, oxygen, and sulfur, or (R6A)C;Le is selected from the group consisting ofRing D is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 7-14 membered saturated or partially unsaturated tricyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Each R8is independently selected from hydrogen, halogen, hydroxyl, -CN, C1-4 alkoxy, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic, C1-C6 haloalkyl, and C1-4 alkyl; or two R8groups and the atom to which they are attached form oxo, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R9is selected from hydrogen, Ci-Ce alkyl, Ci-Cehaloalkyl, C1-3 hydroxyalkyl, Ci-Ce alkoxy, Ci- Ce haloalkoxy, and an optionally substituted C 1-6 aliphatic; orR9is a cyclic group or an optionally substituted C1-6 aliphatic substituted with a cyclic group, wherein the cyclic group is selected from:• phenyl;• a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring;• a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• an 8-10 membered bicyclic hetero aromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• a 5- 12 membered saturated or partially unsaturated bicyclic carbocyclic ring that is optionally bridged or spirocyclic; and• a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the cyclic group is substituted with y instances of RA;each R6Ais independently a C1-6 aliphatic-cyclic or cyclic group, wherein the cyclic group is selected from:• a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• an 8-10 membered bicyclic hetero aromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring that is optionally bridged or spirocyclic; and• a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein R6Ais substituted with y instances of RA;each R6Bis independently halogen, -CN, oxo, -OR, -SR, -NR2, -SO2R, -SO2NR2, -S(O)R, - S(O)NR2, -C(O)R, -CO2R, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)CO2R, -N(R)C(O)R, N(R)C(O)NR2, N(R)C(NR)R, N(R)C(NR)NR2, N(R)NR2, -N(R)SO2NR2, -N(R)SO2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, - P(O)(OR)2, -P(O)R2, or an optionally substituted group selected from Ci-6 aliphatic; a 3- 7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;b is 0, 1, 2, or 3;c is 0, 1, 2, or 3;each RAis independently selected from deuterium, a C1-6 aliphatic group substituted with 0, 1, 2, or 3 groups independently selected from halogen, deuterium, -CN, -NR2, and -OR; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, -CN, -NR2, and -OR; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, -CN, -NR2, and - OR; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, -CN, -NR2, and -OR; a 4- 12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl and heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or 3 groups independently selected C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 hydroxyalkyl, halogen,-CN, -OR, and -NR2; halogen; -CN; -NO2; -OR; SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; -C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)NR2; -N(R)C(NR)NR2; -S(NR)(O)R; -N(R)S(O)2NR2; and -N(R)S(O)2R; ortwo RAon the same atom together form oxo or a cyclic group selected from:• 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; and • a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the cyclic group formed by two RAon the same atom is substituted with 0, 1, 2, or 3 groups independently selected from a Ci-6 aliphatic group substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; halogen; -CN; -NO2; -OR;SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; - C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; - N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; and -N(R)S(O)2R; or two RAon adjacent atoms form a cyclic group selected from:• 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; • a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• phenyl; and• a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the cyclic group formed by two RAon adjacent atoms is substituted with 0, 1, 2, or 3 groups independently selected from a Ci-6 aliphatic group substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; halogen; -CN; -NO2; -OR;SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; - C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; - N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; and -N(R)S(O)2R;each R is independently hydrogen, -C(O)N(CH3)2, -C(O)2CH3, -C(O)2C(CH3)3, -C(O)2CH(CH3)2, -S(O)2CH33, an optionally substituted Ci-6 aliphatic group, an optionally substituted cyclic group, or an optionally substituted Ci-6 alkyl-cyclic group, wherein the cyclic group is selected from:• an optionally substituted phenyl;• an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring;• an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• an optionally substituted 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• an optionally substituted 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and• an optionally substituted 6-11 membered saturated or partially unsaturated bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and / ortwo R groups on the same atom are taken together with the same atom to form a cyclic group selected from:• an optionally substituted 4-7 membered saturated or partially unsaturated carbocyclyl;• an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andan optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfurwherein the optionally substituted R moiety is substituted with 0, 1, 2, 3, or 4 RSub;each RSubis independently selected from Ci-6 aliphatic group substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -N(RN)2, and -O RN; halogen; -CN; -NO2; -ORN; -SRN; -N(RN)2; -S(O)2RN; -S(O)2N(RN)2; -S(O)RN; -S(O)N(RN)2;-C(O)RN; -C(O)ORN; -C(O)N(RN)2; -C(O)N(RN)ORN; -OC(O)RN; -OC(O)N(RN)2; -N(RN)C(O)ORN; -N(RN)C(O)RN; -N(RN)C(O)N(RN)2; -N(RN)C(NRN)N(RN)2;-N(RN)S(O)2N(RN)2; and -N(RN)S(O)2RN; and each RNis independently selected from H and Ci-3 alkyl.

[0011] In certain other aspects, the present invention provides a compound of formula I wherein said compound is of formula I-a, I-b, or I-c:I-cor a pharmaceutically acceptable salt thereof, wherein each of Xi, X2, X3, R1A, R3, Li, L2, L3, L4, L5, a, and Ring C are as defined herein, both singly and in combination.

[0012] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula I or formula I-a, I-b, or I-c and a pharmaceutically acceptable carrier, adjuvant, or diluent.

[0013] In some embodiments, the present invention provides a method of treating a SIK2-mediated disease, disorder, or condition comprising administering to a patient in need thereof, a compound of formula I or formula I-a, I-b, or I-c, or a pharmaceutically acceptable salt thereof.2. Compounds and Definitions:

[0014] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001.

[0015] Compound structures shown throughout the present specification and in the examples or claims contain designations at certain stereocenters which indicate the following: “orl” is intended to cover stereochemically pure compounds wherein the stereochemistry at the stereocenter marked with “orl” is either the stereochemistry shown in the diagram or wherein the marked stereocenter has a configuration opposite to what is shown in the diagram. In structures with stereocenters with the same label such as “orl” the relative stereochemistry between two stereocenters with said label is as drawn, as in compounds 1-36 and 1-371-36 1-37

[0016] Stereocenters marked with “abs” intend to cover material wherein the marked stereocenter is of the stereochemistry shown in the diagram. Stereocenters marked with “&1” or “andl” indicatethat the compound material has a mixture of R and S-configured stereoisomers with respect to the marked stereocenter and is in the same relative configuration to each other if they share the same label such as “andl” or “&1”.

[0017] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle," “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-12 carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0018] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. The term “alkyl” refers to a C1-12 straight or branched saturated aliphatic group. In certain instances, alkyl refers to a C1-8straight or branched saturated aliphatic group or a Ci-6 straight or branched saturated aliphatic group. The term “lower alkyl” refers to a C1-4 straight or branched alkyl group.

[0019] Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl (also referred to interchangeably herein as 2-propyl, iPr, Pr and i-Pr), butyl, isobutyl (also referred to interchangeably herein as 2-butyl, iBu, 'Bu and i-Bu) and tert-butyl (also referred to interchangeably herein as 2-methyl-2-butyl, tBu, ‘Bu and t-Bu).

[0020] The term “alkenyl” refers to a C2-12 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon double bond. In certain instances, alkenyl refers to a C2-8 or a C1-6 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon double bond. The term “lower alkenyl” refers to a C2-4 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon double bond. Alkenyl groups include both cis (Z) and trans (E) regioisomers. Exemplary lower alkenyl groups are vinyl, allyl, 2-propenyl, and butenyl isomers (-CH2CH2CH=CH2, -CH2CH=CHCH3and -CH=CHCH2CH3).

[0021] The term “alkynyl” refers to a C2-12 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon triple bond. In certain instances, alkynyl refers to a C2-8 or a C1-6 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon triple bond. The term “lower alkynyl” refers to a C2-4 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon triple bond. Exemplary lower alkynyl groups are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyL

[0022] The term “haloalkyl” refers to a straight or branched alkyl group that is substituted with one or more halogen atoms. The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.

[0023] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quatemized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)).

[0024] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0025] As used herein, the term “bivalent Ci-8 (or Ci-e) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0026] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., -(CH2)n- wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0027] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0028] The term “halogen” means F, Cl, Br, or I.

[0029] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0030] The terms “heteroaryl” and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, 9 or 10 ring atoms; having 6, 10, or 14 n electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, triazinyl, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl (i.e., l,2,3triazolyl), 1,2,4triazolyl, l,2,5triazolyl, l,3,4triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, l,2,3oxadiazolyl, l,2,4oxadiazolyl, 1,2,5-oxadiazolyl, l,3,4oxadiazolyl, thiazolyl,isothiazolyl, thiadiazolyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, indolizinyl, isoindolin-l-only, l,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-onyl, 2,3-dihydro-lH-pyrrolo[3,4-c]pyridin-l-only, imidazo[l,2-a]pyridyl, imidazo[l,5-a]pyridyl, pyrazolo[l,5-a]pyridyl, pyrrolo[l,2-b]pyridazinyl, pyrrolo[l,2-a]pyrimidinyl, imidazo[l,2-b]pyridazinyl, imidazo[l,2-a]pyrimidinyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4 / 7 quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. A heteroaryl group may be mono- or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0031] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2 / / — py rroly 1), NH (as in pyrrolidinyl), or+NR (as in A-substituted pyrrolidinyl).

[0032] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclylring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3 / 7-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0033] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0034] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0035] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)o 4R0; -(CH2)o- 4OR0; -0(CH2)o-4R°, -O-(CH2)O4C(O)ORO; -(CH2)O4CH(ORO)2; -(CH2)O4SRO; -(CH2)O4Ph, which may be substituted with R°; -(CH2)O 4O(CH2)() iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o- -40(CH2)o- -1 -pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)0-4N(R°)2; -(CH2)0-4N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2)0-4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; -(CH2)0-4N(R°)C(O)OR°; -N(RO)N(RO)C(O)R°; -N(RO)N(RO)C(0)NRO2; -N(R°)N(RO)C(O)OR°; -N(RO)C(NR°)N(RO)2;-(CH2)0-4C(O)R°; -C(S)R°; -(CH2)0-4C(O)OR°; -(CH2)O4C(O)SRO; -(CH2)0-4C(O)OSiR°3; -(CH2)0^OC(O)R°; -OC(O)(CH2)0-4SR°; -(CH2)^4SC(O)R°; -(CH2)0-4C(O)NR°2; -C(S)NRO2; -C(S)SR°; -SC(S)SR°, -(CH2)0-4OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2)0-4SSR°; -(CH2)0-4S(O)2R°; -(CH2)0-4S(O)2OR°; -(CH2)0-4OS(O)2R°; -S(O)2NRO2; -(CH2)0-4S(O)R°; -N(R°)S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NR°2; -(CH2)0-4P(O)2R°; -(CH2)0-4P(O)R°2; -(CH2)0-4OP(O)(OR°)2; -(CH2)0-4OP(O)(OR°)2; -SiR°3; -(C1-4straight or branched alkylene)O-N(R°)2; or -(C1-4straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, Ci-6 aliphatic, -CH2Ph, -0(CH2)o iPh, -CH2-(5-6 membered heteroaryl ring), or a 3-12-membered saturated, partially unsaturated, monocyclic, bicyclic, bridged bicyclic, or spirocyclic, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, monocyclic, bicyclic, bridged bicyclic, or spirocyclic, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0036] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)o-2R*, -(haloR*), -(CH2)o_2OH, -(CH2)o-2OR*, -(CH2)0 2CH(OR’)2; -O(haloR’), -CN, -N3, -(CH2)o-2C(O)R’, -(CH2)0-2C(O)OH, -(CH2)0-2C(O)OR*, -(CH2)O 2SR’, -(CH2)0-2SH, -(CH2)O-2NH2, -(CH2)O-2NHR*, -(CH2)O-2NR*2, -NO2, -SiR*3, -OSiR*3, C(O)SR*, -(C1-4straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-4aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0037] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, -O(C(R*2))2-3O-, or -S(C(R*2))2-3S-, wherein each independent occurrence of R is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)2 3O-, wherein each independent occurrence of R* is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0038] Suitable substituents on the aliphatic group of R include halogen, -R*, (haloR*), OH, -OR’, -O(haloR’), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0039] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -Rj, -NRf2, -C(O)Rf, -C(O)ORf, -C(0)C(0. -C(O)CH2C(O)R†, S(O)2R†, S(O)2NR†2, -C(S)NR†2, -C(NH)NR†2, or -N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0040] Suitable substituents on the aliphatic group of R are independently halogen, -R*, (haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR•2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0041] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are wellknown in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using 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, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0042] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0043] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, Z and E conformational isomers and Ra(or M) and Sa(or P) atropisomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, 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, compounds having the present structures including the replacement of hydrogen bydeuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.

[0044] The structures as drawn represent absolute configurations unless indicated otherwise. The invention contemplates individual enantiomers and diastereomers, enantiomerically enriched enantiomers and diastereomers, and racemic mixtures of enantiomers and diastereomers.

[0045] As used herein, a " SIK2 inhibitor" is a molecule that reduces, inhibits, or otherwise diminishes one or more of the biological activities of SIK2 (e.g., protein phosphorylation). Inhibition using the SIK2 inhibitor does not necessarily indicate a total elimination of the SIK2 activity. Instead, the activity could decrease by a statistically significant amount including, for example, a decrease of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95% or 100% of the activity of SIK2 compared to an appropriate control.

[0046] A compound of the present invention may be tethered to a detectable moiety. It will be appreciated that such compounds are useful as imaging agents. One of ordinary skill in the art will recognize that a detectable moiety may be attached to a provided compound via a suitable substituent. As used herein, the term “suitable substituent” refers to a moiety that is capable of covalent attachment to a detectable moiety. Such moieties are well known to one of ordinary skill in the art and include groups containing, e.g., a carboxylate moiety, an amino moiety, a thiol moiety, or a hydroxyl moiety, to name but a few. It will be appreciated that such moieties may be directly attached to a provided compound or via a tethering group, such as a bivalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties may be attached via click chemistry. In some embodiments, such moieties may be attached via a 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst. Methods of using click chemistry are known in the art and include those described by Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41:2596-99 and Sun et al., Bioconjugate Chem., 2006, 17:52-57.

[0047] As used herein, the term “detectable moiety” is used interchangeably with the term "label" and relates to any moiety capable of being detected, e.g., primary labels and secondary labels. Primary labels, such as radioisotopes (e.g., tritium,32P,33P,35S, or14C), mass-tags, and fluorescent labels are signal generating reporter groups which can be detected without further modifications. Detectable moieties also include luminescent and phosphorescent groups.

[0048] The term “secondary label” as used herein refers to moieties such as biotin and various protein antigens that require the presence of a second intermediate for production of a detectable signal. For biotin, the secondary intermediate may include streptavidin-enzyme conjugates. For antigen labels, secondary intermediates may include antibody-enzyme conjugates. Some fluorescent groups act as secondary labels because they transfer energy to another group in the process of nonradiative fluorescent resonance energy transfer (FRET), and the second group produces the detected signal.

[0049] The terms “fluorescent label”, “fluorescent dye”, and “fluorophore” as used herein refer to moieties that absorb light energy at a defined excitation wavelength and emit light energy at a different wavelength. Examples of fluorescent labels include, but are not limited to: Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 650 / 665), Carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow, Coumarin 343, Cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), Dansyl, Dapoxyl, Dialkylaminocoumarin, 4',5'-Dichloro-2',7'-dimethoxy-fluorescein, DM-NERF, Eosin, Erythrosin, Fluorescein, FAM, Hydroxycoumarin, IRDyes (IRD40, IRD 700, IRD 800), JOE, Lissamine rhodamine B, Marina Blue, Methoxy coumarin, Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, Rhodamine Green, Rhodamine Red, Rhodol Green, 2',4',5',7'-Tetra-bromosulfone-fluorescein, Tetramethyl-rhodamine (TMR), Carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

[0050] The term “mass-tag” as used herein refers to any moiety that is capable of being uniquely detected by virtue of its mass using mass spectrometry (MS) detection techniques. Examples of mass-tags include electrophore release tags such as N-[3-[4’-[(p-Methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecotic Acid, 4’-[2,3,5,6-Tetrafluoro-4-(pentafluorophenoxyl)]methyl acetophenone, and their derivatives. The synthesis and utility of these mass-tags is described in United States Patents 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270. Other examples of masstags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of varyinglength and base composition, oligopeptides, oligosaccharides, and other synthetic polymers of varying length and monomer composition. A large variety of organic molecules, both neutral and charged (biomolecules or synthetic compounds) of an appropriate mass range (100-2000 Daltons) may also be used as mass-tags.

[0051] The terms “measurable affinity” and “measurably inhibit,” as used herein, means a measurable change in a SIK2 protein kinase activity between a sample comprising a compound of the present invention, or composition thereof, and a SIK2 protein kinase, and an equivalent sample comprising a SIK2 protein kinase, in the absence of said compound, or composition thereof.3. Description of Exemplary Embodiments:

[0052] As described above, in certain embodiments, the present invention provides a compound of formula I:Ior a pharmaceutically acceptable salt thereof, wherein:X is N or C;Y is N or C, where when one of X and Y is N and the other of X and Y is C;Each = is a single or double bond;Li is selected from a bond, -O-, -S-, -S(O)2-, -NR1-, -C(O)-, -C(O)NR1-, -NR1C(O)-, -NR1C(O)NR1-, and -[C(R1a)(R1b)]1-2-;L2is selected from a bond, a substituted or unsubstituted alkenylene, -O-, -S-, -S(O)2-, -N= S(O)(CH3)-, -S(O)(CH3)=N-, -S(O)2NR1-, -NR1S(O)2-, -NR1-, -C(O)-, -C(O)NR1-, -NR1C(O)-, -NR1C(O)NR1-, an optionally substituted C3-C6cycloalkyl, an optionally substituted C3-C6heterocycloalkyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and-[C(R2a)(R2b)]1-2-;L3is selected from a bond, a substituted or unsubstituted alkenylene, -O-, -S-, -S(O)2-, -N= S(O)(CH3)-, -S(O)(CH3)=N-, -S(O)2NR1-, -NR1S(O)2-, -NR1-, -C(O)-, -C(O)NR1-, -NR1C(O)-, -NR1C(O)NR1-, an optionally substituted C3-Ce cycloalkyl, an optionally substituted C3-Ce heterocycloalkyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and-[C(R3a)(R3b)]i-2-;L4 is selected from a bond, a substituted or unsubstituted alkenylene, -O-, -S-, -S(O)2-, -N= S(O)(CH3)-, -S(O)(CH3)=N-, -S(O)2NR1-, -NR1S(O)2-, -NR1-, -C(O)-, -C(O)NR1-, - NR^tO)-, -NR1C(O)NR1-, an optionally substituted C3-Ce cycloalkyl, an optionally substituted C3-C6 heterocycloalkyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and-[C(R4a)(R4b)]i-2-;L5 is selected from a bond, -O-, -S-, -S(O)2-, -NR1-, -C(O)-, -C(O)NR1-, -NR1C(O)-, -NR1C(O)NR1-, and -[C(R5a)(R5b)]i-2-;Each R1is independently selected from the group consisting of hydrogen, C1-3 haloalkyl, Ci-3hydroxyalkyl, Co-3alkyl-C3-C6 cycloalkyl, Co-3alkyl-C3-C6 heterocycloalkyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and C1-3 alkyl; wherein Co_3alkyl-C3-Ce cycloalkyl, Co-3alkyl-C3-Ce heterocycloalkyl and Ci-3alkyl are substituted with y instances of RB;each RBis independently halogen, C1-3 alkyl, C1-3 hydroxyalkyl, -CN, oxo, -OR, or -NR2; each y is independently 0, 1, 2, or 3;Rla, Rlb, R2a, R2b, R3a, R3b, R4a, R4b, R5a, and R5bare independently selected from the group consisting of hydrogen, halogen, hydroxyl, N(R )2, C1-3 alkyl, -CN, C1-3 alkoxy, C0-3 alkyl- C3-C6cycloalkyl, Co-3alkyl-C3-Ce heterocycloalkyl, and C1-3 hydroxyalkyl, and C1-3 haloalkyl, wherein Co-3 alkyl-C3-C6 cycloalkyl, Co-3alkyl-C3-C6 heterocycloalkyl and Ci-3alkyl are substituted with y instances of RB; orRlaand Rlb, R2aand R2b, R3aand R3b, R4aand R4b, or R5aand R5b, and the carbon atom to which they are attached may combine to form:a) a 3-7 membered saturated or partially unsaturated bivalent monocyclic carbocyclylene or 4-7 membered saturated or partially unsaturated bivalent heterocyclylene ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 nitrogen atoms in addition to the 1-4 heteroatoms) - substituted with y instances of RB, orb) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene or heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) - substituted with y instances of RB, orRlaand R2a, Rlaand R3a, R2aand R3a, R2aand R4a, R3aand R4a, R3aand R5a, or R4aand R5a, and the atoms to which they are connected may combine to form:a) a 3-7 membered saturated or partially unsaturated bivalent monocyclic carbocyclylene or a 4-7 membered saturated or partially unsaturated bivalent heterocyclylene ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 nitrogen atoms in addition to the 1-4 heteroatoms) - substituted with y instances of RB, orb) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene or heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) - substituted with y instances of RB;Xi and X2 are each selected from N and CR2provided when Y is N, Xi is CR2;each R2is independently selected from hydrogen, OH, C1-3 alkyl, C1-3 alkoxy, and halogen; X3 is selected from O, S, N, NR7, and CR2, provided when X3 is selected from O, S, and NR7, X and Y areC;R7is hydrogen or C 1-3 alkyl;Ring C is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- 12 membered saturated or partially unsaturated bicyclic heterocyclyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R1Ais independently halogen, -CN, oxo, -OR, -SR, -NR2, -SO2R, -SO2NR2, -S(O)R, - S(O)NR2, -C(O)R, -CO2R, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)CO2R, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)R, -N(R)C(NR)NR2, -N(R)NR2, -N(R)SO2NR2, -N(R)SO2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, - P(O)(OR)2, -P(O)R2, C1-C6 haloalkyl, C1-3 hydroxyalkyl, C3-C6 halocycloalkyl, Ci-Ce haloalkoxy, or an optionally substituted group selected from Ci-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;a is 0, 1, 2, or 3;R3is -C(O)-L6, -S(O)2- 6, an optionally substituted Ci-6 aliphatic, an optionally substituted Ci-6(R6B)baliphatic substituted with (R6A)C,an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, orL6is selected from the group consisting ofRing D is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-12 memberedsaturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 7-14 membered saturated or partially unsaturated tricyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Each R8is independently selected from hydrogen, halogen, hydroxyl, -CN, C1-4alkoxy, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic, C1-C6haloalkyl, and C1-4alkyl; or two R8groups and the atom to which they are attached form oxo, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R9is selected from hydrogen, Ci-Ce alkyl, Ci-Cehaloalkyl, C1-3 hydroxyalkyl, Ci-Ce alkoxy, Ci- Ce haloalkoxy, and an optionally substituted C 1-6 aliphatic; orR9is a cyclic group or an optionally substituted C1-6 aliphatic substituted with a cyclic group, wherein the cyclic group is selected from:• phenyl;• a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring;• a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• an 8-10 membered bicyclic hetero aromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• a 5- 12 membered saturated or partially unsaturated bicyclic carbocyclic ring that is optionally bridged or spirocyclic; and• a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the cyclic group is substituted with y instances of RA;each R6Ais independently a Ci-6 aliphatic-cyclic or cyclic group, wherein the cyclic group is selected from:• a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• an 8-10 membered bicyclic hetero aromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring that is optionally bridged or spirocyclic; and• a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein R6Ais substituted with y instances of RA;each R6Bis independently halogen, -CN, oxo, -OR, -SR, -NR2, -SO2R, -SO2NR2, -S(O)R, - S(O)NR2, -C(O)R, -CO2R, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)CO2R, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)R, -N(R)C(NR)NR2, -N(R)NR2, -N(R)SO2NR2, -N(R)SO2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, - P(O)(OR)2, -P(O)R2, or an optionally substituted group selected from C1-6 aliphatic; a 3- 7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;b is 0, 1, 2, or 3;c is 0, 1, 2, or 3;each RAis independently selected from deuterium, a C1-6 aliphatic group substituted with 0, 1, 2, or 3 groups independently selected from halogen, deuterium, -CN, -NR2, and -OR; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, -CN, -NR2, and -OR; a 3-8 memberedsaturated or partially unsaturated monocyclic heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, -CN, -NR2, and -OR; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, -CN, -NR2, and -OR; a 4- 12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl and heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or 3 groups independently selected C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 hydroxyalkyl, halogen, -CN, -OR, and -NR2; halogen; -CN; -NO2; -OR;SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; -C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)NR2; -N(R)C(NR)NR2; -S(NR)(O)R; -N(R)S(O)2NR2; and -N(R)S(O)2R; ortwo RAon the same atom together form oxo or a cyclic group selected from:• 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; and • a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the cyclic group formed by two RAon the same atom is substituted with 0, 1, 2, or 3 groups independently selected from a C1-6 aliphatic group substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; halogen; CN; NO2; OR;SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; - C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; - N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; and -N(R)S(O)2R; or two RAon adjacent atoms form a cyclic group selected from:• 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; • a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• phenyl; and• a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the cyclic group formed by two RAon adjacent atoms is substituted with 0, 1, 2, or 3 groups independently selected from a Ci-6 aliphatic group substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; halogen; -CN; -NO2; -OR;SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; - N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; and -N(R)S(O)2R;each R is independently hydrogen, -C(O)N(CH2)2, -C(O)2CH3, -C(O)2C(CH3)3, -C(O)2CH(CH3)2, -S(O)2CH33, an optionally substituted C1-6 aliphatic group, an optionally substituted cyclic group, or an optionally substituted C1-6 alkyl-cyclic group, wherein the cyclic group is selected from:• an optionally substituted phenyl;• an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring;• an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• an optionally substituted 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• an optionally substituted 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and• an optionally substituted 6-11 membered saturated or partially unsaturated bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and / ortwo R groups on the same atom are taken together with the same atom to form a cyclic group selected from:• an optionally substituted 4-7 membered saturated or partially unsaturated carbocyclyl;• an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and• an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the optionally substituted R moiety is substituted with 0, 1, 2, 3, or 4 RSub; each RSubis independently selected from Ci-6 aliphatic group substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -N(RN)2, and -O RN; halogen; -CN; - NO2; -ORN; -SRN; -N(RN)2; -S(O)2RN; -S(O)2N(RN)2; -S(O)RN; -S(O)N(RN)2; -C(O)RN; -C(O)ORN; -C(O)N(RN)2; -C(O)N(RN)ORN; -OC(O)RN; -OC(O)N(RN)2; -N(RN)C(O)ORN; -N(RN)C(O)RN; -N(RN)C(O)N(RN)2; -N(RN)C(NRN)N(RN)2; -N(RN)S(O)2N(RN)2; and -N(RN)S(O)2RN; and each RNis independently selected from H and Ci-3 alkyl.

[0053] In some embodiments, the compound of formula I is a compound of formula La, I-b, or Lc:I-a I-bI-cor a pharmaceutically acceptable salt thereof, wherein each of Xi, X2, X3, R1A, R3, Li, L2, L3, L4, L5, a, and Ring C are as defined herein, both singly and in combination, and Ring C is a 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0054] In some embodiments, the compound of formula I-a, I-b, or I-c:I-cor a pharmaceutically acceptable salt thereof, wherein each of Xi, X2, X3, R1A, R3, Li, L2, L3, L4, L5, a, as defined herein, both singly and in combination, and Ring C is a 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0055] In some embodiments, the compound of formula I-a, I-b, or I-c:I-cor a pharmaceutically acceptable salt thereof, wherein each of Xi, X2, X3, R1A, R3, Li, L2, L3, L4, L5, a, as defined herein, both singly and in combination, and Ring C is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0056] In some embodiments, the compound of formula I-a, I-b, or I-c:or a pharmaceutically acceptable salt thereof, wherein each of Xi, X2, X3, R1A, R3, Li, L2, L3, L4, L5, a, as defined herein, both singly and in combination, and Ring C is an 8-10 membered bicyclic heteroaryl ring having 1^4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0057] As defined generally above, X is N or C.

[0058] In some embodiments, X is N. In some embodiments, X is C.

[0059] As defined generally above, Y is N or C.

[0060] In some embodiments, X is N. In some embodiments, X is C.

[0061] In certain embodiments, one of X and Y is N and the other of X and Y is C;

[0062] In some embodiments, X and Y are as depicted in the compounds of Table 1, below.

[0063] As defined generally above, is a single or double bond.

[0064] In some embodiments, = is a single bond. In some embodiments, = is a double bond.

[0065] In some embodiments, = is as depicted in the compounds of Table 1, below.

[0066] As defined generally above, Xi and X2 are independently selected from N and CR2provided that none are N or only one of Xi and X2 may be N.

[0067] In some embodiments, Xi is N. In some embodiments, Xi is CR2.

[0068] In some embodiments, X2 is N. In some embodiments, X2 is CR2.

[0069] In some embodiments, Xi, and X2 are CR2. In some embodiments, Xi is N, and X2 and X3 are CR2. In some embodiments, X2 is N, and Xi and X3 are CR2. In some embodiments, X3 is N, and Xi and X2 are CR2.

[0070] In some embodiments, Xi is as depicted in the compounds of Table 1, below.

[0071] In some embodiments, X2 is as depicted in the compounds of Table 1, below

[0072] In some embodiments, X3 is selected from O, N, S, NR7and CR2;

[0073] In some embodiments, X3 is O.

[0074] In some embodiments, X3 is S.

[0075] In some embodiments, X3 is NR7.

[0076] In some embodiments, X3 is N.

[0077] In some embodiments, X3is CR2.

[0078] In some embodiments, X3 is as depicted in the compounds of Table 1, below.

[0079] As defined generally above, each R2is independently selected from hydrogen, OH, C1-3 alkyl, C1-3 alkoxy, and halogen.

[0080] In some embodiments, R2is hydrogen. In some embodiments, R2is OH. In some embodiments, R2is C1-3 alkyl. In some embodiments, R2is C1-3 alkoxy. In some embodiments, R2is halogen.

[0081] In some embodiments, R2is hydrogen, F, Cl, CH3, OCH3, or CH2CH3.

[0082] In some embodiments, R2is F.

[0083] In some embodiments, R2is Cl.

[0084] In some embodiments, R2is CH3.

[0085] In some embodiments, R2is OCH3.

[0086] In some embodiments, R2is CH2CH3.

[0087] In some embodiments, R2is CH(CH3)2.

[0088] In some embodiments, R2is as depicted in the compounds of Table 1, below.

[0089] As defined generally above, R7is hydrogen or C1–4alkyl.

[0090] In some embodiments, R7is hydrogen. In some embodiments, R7is C1–4alkyl.

[0091] In some embodiments, R7is methyl.

[0092] In some embodiments, R7is as depicted in the compounds of Table 1, below.

[0093] As defined generally above, Ring C is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0094] In some embodiments, Ring C is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 7-12 memberedsaturated or partially unsaturated bicyclic heterocyclyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0095] In some embodiments, Ring C is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 9-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9-membered partially unsaturated bicyclic heterocyclyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0096] In some embodiments, Ring C is a 5-membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0098] In some embodiments, Ring C is

[0099] In some embodiments, Ring C is as depicted in the compounds of Table 1, below.

[0100] As defined generally above, Ring D is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 7-14 membered saturated or partially unsaturated tricyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0101] In some embodiments, Ring D is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic. In some embodiments, Ring D is 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring D is a 7-14 membered saturated or partially unsaturated tricyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0102] In some embodiments, Ring D is a 3-4 membered saturated or partially unsaturated monocyclic carbocyclic.

[0103] In some instances, Ring D isA>;or, where b is 0, 1, 2, or 3, and c is 1.

[0104] In some embodiments, Ring D is as depicted in the compounds of Table 1, below.

[0105] As defined generally above, each R8is independently selected from hydrogen, halogen, hydroxyl, -CN, CM alkoxy, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic, Ci-Ce haloalkyl, and CIM alkyl; or two R8groups and the atom to which they are attached can form oxo, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each R8is independently selected from hydrogen, halogen, hydroxyl, -CN, CIM alkoxy, Ci-Ce haloalkyl, and CIM alkyl; or two R8groups and the atom to which they are attached can form oxo, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0106] In some embodiments, at least one R8is hydrogen. In some embodiments, at least one R8is halogen. In some embodiments, at least one R8is hydroxyl. In some embodiments, at least one R8is -CN. In some embodiments, at least one R8is CIM alkoxy. In some embodiments, at least one R8is Ci 4 alkyl. In some embodiments, at least one R8is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic. In some embodiments, two R8groups and the atom to which they are attached form oxo. In some embodiments, at least one R8is Ci-Ce haloalkyl. In some embodiments, two R8groups and the atom to which they are attached form a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, two R8groups and the atom to which they are attached form a 3-8 membered saturated or partiallyunsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0107] As defined generally above, R9is selected from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1–3hydroxyalkyl, C1-C6alkoxy, C1-C6haloalkoxy, and an optionally substituted C1–6aliphatic; or R9is a cyclic group or an optionally substituted Ci-6 aliphatic substituted with a cyclic group, wherein the cyclic group is selected from:• phenyl;• a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring;• a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• a 5- 12 membered saturated or partially unsaturated bicyclic carbocyclic ring that is optionally bridged or spirocyclic; and• a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the cyclic group is substituted with y instances of RA.

[0108] In some embodiments, R9is hydrogen. In some embodiments, R9is C1-C6alkyl. In some embodiments, R9is Ci-Ce haloalkyl. In some embodiments, R9is C1-3 hydroxyalkyl. In some embodiments, R9is Ci-Ce alkoxy. In some embodiments, R9is Ci-Ce haloalkoxy. In some embodiments, R9is an optionally substituted Ci-6 aliphatic. In some embodiments, R9is a cyclic group. In some embodiments, R9is an optionally substituted C1-6 aliphatic substituted with a cyclic group. In some embodiments, R9is phenyl. In some embodiments, the cyclic group of R9is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, the cyclic group of R9is a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, the cyclic group of R9is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the cyclic group of R9is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the cyclic group of R9is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the cyclic group of R9is a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring that is optionally bridged or spirocyclic. In some embodiments, the cyclic group of R9is a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the cyclic group of R9is substituted with y instances of RA.

[0109] As defined generally above, each R6Ais independently a Ci-6 aliphatic-cyclic or cyclic group, wherein the cyclic group is selected from:• a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, • phenyl;• a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• a 5- 12 membered saturated or partially unsaturated bicyclic carbocyclic ring that is optionally bridged or spirocyclic; and• a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0110] In some embodiments, at least one R6Ais a Ci-6 aliphatic group. In some embodiments, at least one R6Ais a Ci-6 aliphatic-cyclic group. In some embodiments, at least one R6Ais a 3-8membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, at least one R6Ais phenyl. In some embodiments, at least one R6Ais a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, at least one R6Ais a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, at least one R6Ais an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, at least one R6Ais a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, at least one R6Ais a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring that is optionally bridged or spirocyclic. In some embodiments, at least one R6Ais a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, there is only one R6A(i.e., c is 1). In specific cases of that embodiment, the one R6Ais a Ci-6 aliphatic group. In specific cases of that embodiment, the one R6Ais a Ci-6 aliphatic-cyclic group. In specific cases of that embodiment, the one R6Ais a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In specific cases of that embodiment, the one R6Ais phenyl. In specific cases of that embodiment, the one R6Ais a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In specific cases of that embodiment, the one R6Ais a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In specific cases of that embodiment, the one R6Ais an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In specific cases of that embodiment, the one R6Ais a 7- 12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In specific cases of that embodiment, the one R6Ais a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring that is optionally bridged or spirocyclic. In specific cases of that embodiment, the one R6Ais a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0111] In some embodiments, at least one (or when c is 1, the only) R6Ais a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 9-membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0112] In some embodiments, at least one (or when c is 1, the only) R6Ais a 5-6 membered monocyclic heteroaromatic ring having 1-3 nitrogen and 0-1 sulfur heteroatoms or a 9-membered bicyclic heteroaromatic ring having 1-2 nitrogen heteroatoms.

[0113] In some embodiments, at least one (or when c is 1, the only) R6Ais substituted with y instances of RA. In some cases, y is 0, i.e„ R6Ais unsubstituted. In some cases, y is 1 or 2.

[0114] In some embodiments, at least one (or when c is 1, the only) R6Ais

[0115] In some embodiments, at least one (or when c is 1, the only) R6Ais

[0116] In some embodiments, at least one (or when c is 1, the only) R6Ais as depicted in the compounds of Table 1, below.

[0117] In some embodiments, at least one (or when c is 1, the only) R6Aand its RAsubstituents is

[0118] In some embodiments, at least one (or when c is 1, the only) R6Aand its RAsubstituents is as depicted in the compounds of Table 1, below.

[0119] As defined generally above, c is 0, 1, 2 or 3.

[0120] In some embodiments, c is 0. In some embodiments, c is 1. In some embodiments, c is 2. In some embodiments, c is 3.

[0121] In some embodiments, c is 1 or 2. In some embodiments, c is 2 or 3.

[0122] In some embodiments, c is depicted in the compounds of Table 1, below.

[0123] As defined generally above, each R6Bis independently halogen, oxo, -OR, -SR, -NR2, -SO2R, -SO2NR2, -S(O)R, -S(O)NR2, -C(O)R, -CO2R, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)CO2R, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)R, -N(R)C(NR)NR2, -N(R)NR2, -N(R)SO2NR2, -N(R)SO2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(OR)2, -P(O)R2, or an optionally substituted group selected from C1-6 aliphatic; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0124] In some embodiments, at least one R6Bis halogen. In some embodiments, at least one R6Bis oxo. In some embodiments, at least one R6Bis -OR. In some embodiments, at least one R6Bis -SR. In some embodiments, at least one R6Bis -NR2. In some embodiments, at least one R6Bis -SO2R. In some embodiments, at least one R6Bis -SO2NR2. In some embodiments, at least one R6Bis -S(O)R. In some embodiments, at least one R6Bis -S(O)NR2. In some embodiments, at least one R6Bis -C(O)R. In some embodiments, at least one R6Bis -CO2R. In some embodiments, at least one R6Bis -C(O)NR2. In some embodiments, at least one R6Bis -C(O)N(R)OR. In some embodiments, at least one R6Bis -OC(O)R. In some embodiments, at least one R6Bis -OC(O)NR2. In some embodiments, at least one R6Bis -N(R)CO2R. In some embodiments, at least one R6Bis -N(R)C(O)R. In some embodiments, at least one R6Bis -N(R)C(O)NR2. In some embodiments, at least one R6Bis -N(R)C(NR)R. In some embodiments, at least one R6Bis -N(R)C(NR)NR2. In some embodiments, at least one R6Bis -N(R)NR2. In some embodiments, at least one R6Bis -N(R)SO2NR2. In some embodiments, at least one R6Bis -N(R)SO2R. In some embodiments, at least one R6Bis -N=S(O)R2. In some embodiments, at least one R6Bis -S(NR)(O)R. In some embodiments, at least one R6Bis -N(R)S(O)R. In some embodiments, at least one R6Bis -N(R)CN. In some embodiments, at least one R6Bis -P(O)(OR)2. In some embodiments, at least one R6Bis -P(O)R2. In some embodiments, at least one R6Bis an optionally substituted group selected from C1-6 aliphatic. In some embodiments, at least one R6Bis a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, at least one R6Bis a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, at least one R6Bis a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur. In some embodiments, there is only one R6B(i.e., b is 1). In specific cases of that embodiment, the one R6Bis halogen. In specific cases of that embodiment, the one R6Bis oxo. In specific cases of that embodiment, the one R6Bis -OR. In specific cases of that embodiment, the one R6Bis -SR. In specific cases of that embodiment, the one R6Bis -NR2. In specific cases of that embodiment, the one R6Bis -SO2R. In specific cases of that embodiment, the one R6Bis -SO2NR2. In specific cases of that embodiment, the one R6Bis -S(O)R. In specific cases of that embodiment, the one R6Bis -S(O)NR2. In specific cases of that embodiment, the one R6Bis -C(O)R. In specific cases of that embodiment, the one R6Bis -CO2R. In specific cases of that embodiment, the one R6Bis -C(O)NR2. In specific cases of that embodiment, the one R6Bis -C(O)N(R)OR. In specific cases of that embodiment, the one R6Bis -OC(O)R. In specific cases of that embodiment, the one R6Bis -OC(O)NR2. In specific cases of that embodiment, the one R6Bis -N(R)CO2R. In specific cases of that embodiment, the one R6Bis -N(R)C(O)R. In specific cases of that embodiment, the one R6Bis -N(R)C(O)NR2. In specific cases of that embodiment, the one R6Bis -N(R)C(NR)R. In specific cases of that embodiment, the one R6Bis -N(R)C(NR)NR2. In specific cases of that embodiment, the one R6Bis -N(R)NR2. In specific cases of that embodiment, the one R6Bis -N(R)SO2NR2. In specific cases of that embodiment, the one R6Bis -N(R)SO2R. In specific cases of that embodiment, the one R6Bis -N=S(O)R2. In specific cases of that embodiment, the one R6Bis -S(NR)(O)R. In specific cases of that embodiment, the one R6Bis -N(R)S(O)R. In specific cases of that embodiment, the one R6Bis -N(R)CN. In specific cases of that embodiment, the one R6Bis -P(O)(OR)2. In specific cases of that embodiment, the one R6Bis -P(O)R2. In specific cases of that embodiment, the one R6Bis an optionally substituted group selected from Ci-6 aliphatic. In specific cases of that embodiment, the one R6Bis a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In specific cases of that embodiment, the one R6Bis a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In specific cases of that embodiment, the one R6Bis a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0125] In some embodiments, at least one (or when b is 1, the only) R6Bis hydrogen. In some embodiments, at least one (or when b is 1, the only) R6Bis C1–4alkyl. In some embodiments, at least one (or when b is 1, the only) R6Bis C1–4haloalkyl. In some embodiments, at least one (or when b is 1, the only) R6Bis oxo.

[0126] In some embodiments, at least one (or when b is 1, the only) R6Bis hydrogen, F, Cl, CH3. or oxo.

[0127] In some embodiments, at least one (or when b is 1, the only) R6Bis F.

[0128] In some embodiments, at least one (or when b is 1, the only) R6Bis Cl.

[0129] In some embodiments, at least one (or when b is 1, the only) R6Bis CH3.

[0130] In some embodiments, at least one (or when b is 1, the only) R6Bis as depicted in the compounds of Table 1, below.

[0131] As defined generally above, b is 0, 1, 2, or 3.

[0132] In some embodiments, b is 0. In some embodiments, b is 1. In some embodiments, b is 2. In some embodiments, b is 3.

[0133] In some embodiments, b is 1 or 2. In some embodiments, b is 2 or 3.

[0134] In some embodiments, b is depicted in the compounds of Table 1, below.

[0135] In some embodiments, each RAis independently selected from deuterium, a C1-6 aliphatic group substituted with 0, 1, 2, or 3 groups independently selected from halogen, deuterium, -CN, -NR2, and -OR; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, -CN, -NR2, and -OR; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, -CN, -NR2, and -OR; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, -CN, -NR2, and -OR; a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl and heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or3 groups independently selected C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 hydroxyalkyl, halogen, -CN, -OR, and -NR2; halogen; -CN; -NO2; -OR; SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; - C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)NR2; -N(R)C(NR)NR2; -S(NR)(O)R; -N(R)S(O)2NR2; and -N(R)S(O)2R; or two RAon the same atom together form oxo or a cyclic group selected from:• a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; and • a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the cyclic group formed by two RAon the same atom is substituted with 0, 1, 2, or 3 groups independently selected from a Ci-6 aliphatic group substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; halogen; -CN; -NO2; -OR;SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; - C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; - N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; and -N(R)S(O)2R; or two RAon adjacent atoms form a cyclic group selected from:• a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; • a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• phenyl; and• a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the cyclic group formed by two RAon adjacent atoms is substituted with 0, 1, 2, or 3 groups independently selected from a C1-6 aliphatic group substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; halogen; -CN; -NO2; -OR; -SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; - C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; and -N(R)S(O)2R.

[0136] In some embodiments, at least one RAis deuterium. In some embodiments, at least one RAis a C1-6 aliphatic group substituted with 0, 1, 2, or 3 groups independently selected from halogen, deuterium, -CN, -NR2, and -OR. In some embodiments, at least one RAis a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, -CN, -NR2, and -OR. In some embodiments, at least one RAis a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, -CN, -NR2, and -OR. In some embodiments, at least one RAis a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-3 alkyl, C1–3haloalkyl, -CN, -NR2, and -OR. In some embodiments, at least one RAis a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl and heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or3 groups independently selected C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 hydroxyalkyl, halogen, -CN, -OR, and -NR2. In some embodiments, at least one RAis halogen. In some embodiments, at least one RAis -CN. In some embodiments, at least one RAis -NO2. In some embodiments, at least one RAis -OR. In some embodiments, at least one RAis -SR. In some embodiments, at least one RAis -NR2. In some embodiments, at least one RAis -S(O)2R. In some embodiments, at least one RAis -S(O)2NR2. In some embodiments, at least one RAis -S(O)R. In some embodiments, at least one RAis -S(O)NR2. In some embodiments, at least one RAis -C(O)R. In some embodiments, at least one RAis -C(O)OR. In some embodiments, at least one RAis -C(O)NR2. In some embodiments, at least one RAis -C(O)N(R)OR. In some embodiments, at least one RAis -OC(O)R. In some embodiments, at least one RAis -OC(O)NR2. In some embodiments, at least one RAis -N(R)C(O)OR. In some embodiments, at least one RAis -N(R)C(O)R. In some embodiments, at least one RAis -N(R)C(O)NR2. In some embodiments, at least one RAis -N(R)C(NR)NR2. In some embodiments, at least one RAis -S(NR)(O)R. In some embodiments, at least one RAis -N(R)S(O)2NR2. In some embodiments, at least one RAis -N(R)S(O)2R. In some embodiments, two RAon the same atom together form oxo. In some embodiments, two RAon the same atom together form a cyclic group. In some embodiments, two RAon the same atom together form a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, two RAon the same atom together form a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the cyclic group formed by two RAon the same atom is substituted with 0, 1, 2, or 3 groups independently selected from a C1-6 aliphatic group substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; halogen; -CN; -NO2; -OR;SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; -C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; and -N(R)S(O)2R. In some embodiments, two RAon adjacent atoms form a cyclic group. In some embodiments, two RAon adjacent atoms form a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, two RAon adjacent atoms form a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two RAon adjacent atoms form a phenyl. In some embodiments, two RAon adjacent atoms form a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the cyclic group formed by two RAon adjacent atoms is substituted with 0, 1, 2, or 3 groups independently selected from a Ci-6 aliphatic group substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; halogen; -CN; -NO2; -OR;SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; - C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; and -N(R)S(O)2R.

[0137] In some embodiments, at least one (or, when y is 1, the only) RAis halogen; -CN; -OR; a Ci-6 aliphatic group substituted with 0, 1, 2, or 3 groups independently selected from halogen, deuterium, -CN, -NR2, and -OR; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, -CN, -NR2, and -OR; or a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl and heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or3 groups independently selected C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 hydroxyalkyl, halogen, -CN, -OR, and -NR2.

[0138] In some embodiments, at least one (or, when y is 1, the only) RAis fluoro, chloro, -CN, methyl, -CD3, -CH2F, -CHF2, -CF3, -C(CH3)OH, cyclopropyl, -OMe, -OiPr, -OCHF2, -SF6,

[0139] In some embodiments, at least one (or, when y is 1, the only) RAis as depicted in the compounds of Table 1, below.

[0140] As defined generally above, each R1is independently selected from the group consisting of hydrogen, C1-3 haloalkyl, C1-3 hydroxyalkyl, C0-3 alkyl-Ca-Ce cycloalkyl, C0-3 alkyl-C3-C6 heterocycloalkyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and C1-3 alkyl; wherein C0-3 alkyl-C3-C6 cycloalkyl, C0-3 alkyl-C3-C6 heterocycloalkyl and C1-3 alkyl are substituted with y instances of RB.

[0141] In some embodiments, at least one or each R1is hydrogen. In some embodiments, at least one R1is C1-3 haloalkyl. In some embodiments, at least one or each R1is C1-3 hydroxyalkyl. In some embodiments, at least one or each R1is C0-3 alkyl-C3-C6 cycloalkyl substituted with y instances of RB. In some embodiments, at least one or each R1is C0-3 alkyl-C3-C6 heterocycloalkyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) substituted with y instances of RB. In some embodiments, at least one or each R1is C1-3 alkyl substituted with y instances of RB.

[0142] In some embodiments, at least one or each R1is depicted in the compounds of Table 1, below.

[0143] As defined generally above, each RBis independently halogen, C1-3 alkyl, hydroxy-Ci-3 alkyl, -CN, oxo, -OR, or -NR2.

[0144] In some embodiments, at least one or each RBis halogen. In some embodiments, at least one or each RBis C1-3 alkyl. In some embodiments, at least one or each RBis hydroxy-Ci-3 alkyl. In some embodiments, at least one or each RBis -CN. In some embodiments, at least one or each RBis oxo. In some embodiments, at least one or each RBis -OR. In some embodiments, at least one or each RBis -NR2.

[0145] In some embodiments, at least one or each RBis depicted in the compounds of Table 1, below.

[0146] As defined generally above, each y is independently 0, 1, 2, or 3.

[0147] In some embodiments, y is 0. In some embodiments, y is 1. In some embodiments, y is 2. In some embodiments, y is 3. In some embodiments, y is 0 or 1. In some embodiments, y is 1 or 2. In some embodiments, y is 2 or 3.

[0148] In some embodiments, each y is depicted in the compounds of Table 1, below.

[0149] As defined generally above, each R1Aare independently halogen, -CN, oxo, -OR, -SR, -NR2, -SO2R, -SO2NR2, -S(O)R, -S(O)NR2, -C(O)R, -CO2R, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)CO2R, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)R, -N(R)C(NR)NR2, -N(R)NR2, -N(R)SO2NR2, -N(R)SO2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -P(O)(OR)2, -P(O)R2, C1-C6haloalkyl, C1–3hydroxyalkyl, C3-C6halocycloalkyl, C1-C6haloalkoxy, or an optionally substituted group selected from Ci-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0150] In some embodiments, at least one (or when a is 1, the only) R1Ais CH2CH3. In some embodiments, at least one (or when a is 1, the only) R1Ais CH3. In some embodiments, at least one (or when a is 1, the only) R1Ais CF3. In some embodiments, at least one (or when a is 1, the only) R1Ais CHF2. In some embodiments, at least one (or when a is 1, the only) R1Ais CH2CF3. In some embodiments, at least one (or when a is 1, the only) R1Ais CH2CHF2.

[0151] In some embodiments, each R1Ais as depicted in the compounds of Table 1, below.

[0152] In some embodiments, Ring C together with its R1Aand Ls substituents is as depicted in the compounds of Table 1, below.

[0153] In some embodiments, at least one (or when a is 1, the only) R1Ais halogen. In some embodiments, at least one (or when a is 1, the only) R1Ais -CN. In some embodiments, at least one (or when a is 1, the only) R1Ais oxo. In some embodiments, at least one (or when a is 1, the only) R1Ais -OR. In some embodiments, at least one (or when a is 1, the only) R1Ais -SR. In some embodiments, at least one (or when a is 1, the only) R1Ais -NR2. In some embodiments, at least one (or when a is 1, the only) R1Ais -SO2R. In some embodiments, at least one (or when a is 1, the only) R1Ais -SO2NR2. In some embodiments, at least one (or when a is 1, the only) R1Ais -S(O)R. In some embodiments, at least one (or when a is 1, the only) R1Ais -S(O)NR2. In some embodiments, at least one (or when a is 1, the only) R1Ais -C(O)R. In some embodiments,at least one (or when a is 1, the only) R1Ais -CO2R. In some embodiments, at least one (or when a is 1, the only) R1Ais -C(O)NR2. In some embodiments, at least one (or when a is 1, the only) R1Ais -C(O)N(R)OR. In some embodiments, at least one (or when a is 1, the only) R1Ais -OC(O)R. In some embodiments, at least one (or when a is 1, the only) R1Ais -OC(O)NR2. In some embodiments, at least one (or when a is 1, the only) R1Ais -N(R)CO2R. In some embodiments, at least one (or when a is 1, the only) R1Ais -N(R)C(O)R. In some embodiments, at least one (or when a is 1, the only) R1Ais -N(R)C(O)NR2. In some embodiments, at least one (or when a is 1, the only) R1Ais -N(R)C(NR)R. In some embodiments, at least one (or when a is 1, the only) R1Ais -N(R)C(NR)NR2. In some embodiments, at least one (or when a is 1, the only) R1Ais -N(R)NR2. In some embodiments, at least one (or when a is 1, the only) R1Ais –N(R)SO2NR2. In some embodiments, at least one (or when a is 1, the only) R1Ais -N(R)SO2R. In some embodiments, at least one (or when a is 1, the only) R1Ais -N=S(O)R2. In some embodiments, at least one (or when a is 1, the only) R1Ais -S(NR)(O)R. In some embodiments, at least one (or when a is 1, the only) R1Ais -N(R)S(O)R. In some embodiments, at least one (or when a is 1, the only) R1Ais -N(R)CN. In some embodiments, at least one (or when a is 1, the only) R1Ais -P(O)(OR)2. In some embodiments, at least one (or when a is 1, the only) R1Ais -P(O)R2. In some embodiments, at least one (or when a is 1, the only) R1Ais C1-C6haloalkyl. In some embodiments, at least one (or when a is 1, the only) R1Ais C1–3hydroxyalkyl. In some embodiments, at least one (or when a is 1, the only) R1Ais C3-C6halocycloalkyl. In some embodiments, at least one (or when a is 1, the only) R1Ais C1-C6haloalkoxy. In some embodiments, at least one (or when a is 1, the only) R1Ais an optionally substituted C1-6 aliphatic. In some embodiments, at least one (or when a is 1, the only) R1Ais an optionally substituted phenyl. In some embodiments, at least one (or when a is 1, the only) R1Ais an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, at least one (or when a is 1, the only) R1Ais an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, at least one (or when a is 1, the only) R1Ais an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0154] In some embodiments, at least one (or when a is 1, the only) R1Ais halogen, -CN, oxo, -OR, -SO2R, -C(O)NR2, an optionally substituted Ci-6 alkyl, a 3-7 membered saturatedmonocyclic carbocyclic ring, or an optionally substituted 3-7 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0155] In some embodiments, at least one (or when a is 1, the only) R1Ais halogen, -CN, -C(O)NR2, an optionally substituted Ci-6 alkyl, a 3-7 membered saturated monocyclic carbocyclic ring, or an optionally substituted 3-7 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0156] In some embodiments, at least one (or when a is 1, the only) R1Ais fluoro, chloro, -CN, oxo, -OMe, -O(CH2)2NMe2, -O(CH2)2NEt2, –O(CH2)2pyrrolidinyl, -O(CH2)2piperidinyl, –SO2cyclopropyl, –SO2Ph, –C(O)NH(CH2)2NMe2, -C(O)NH(CH2)3NMe2, methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, isopentyl, cyclopentyl, cyclobutyl, methyloxycyclobutyl, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CH2NHMe, -CH2NMeCO2tBu, -CH2SO2Me, -CH2CO2H, -CH2CO2Me, -CH2CONHMe, -CH2CONMe2, -CH2CN, -CH(Me)CN, -CH(Me)2CN, –CH2cyclobutyl, –CH2(methyloxycyclobutyl), –CH2oxetanyl, –CH2(methyloxetanyl), –CH2(fluorooxetanyl), –CH2azetidinyl, –CH2tetrahydrofuranyl, –CH2pyrrolidinyl, -CH2(N-methylpyrrolidinyl), –CH2pyrazolyl, –CH2tetrahydro-2H-pyranyl, –CH2morpholinyl, -CH2(N-methylmorpholinyl), –CH2(N-methylpiperazinyl), –CH2(N,N-dimethylpiperazinyl), -CH2(N-acetylpiperazinyl), –CH2pyridyl, benzyl, CH2(cyclopropylenyl)CN, -(CH2)2pyrrolidin-2-onyl, –(CH2)2CN, –(CH2)2NH2, –(CH2)2oxetanyl, -(CH2)2azetidinyl, -(CH2)3NMe2, piperazinyl, or N-methylpiperazinyl.

[0157] In some embodiments, at least one (or when a is 1, the only) R1Ais fluoro, chloro, -CN, -C(O)NH(CH2)2NMe2, -C(O)NH(CH2)3NMe2, methyl, ethyl, propyl, isopropyl, isobutyl, tertbutyl, isopentyl, cyclopentyl, cyclobutyl, -CHF2, -CF3, piperazinyl, or N-methylpiperazinyl.

[0158] In some embodiments, each R1Ais as depicted in the compounds of Table 1, below.

[0159] As defined generally above, a is 0, 1, 2, or 3.

[0160] In some embodiments, a is 0. In some embodiments, a is 1. In some embodiments, a is 2. In some embodiments, a is 3.

[0161] In some embodiments, a is 1 or 2. In some embodiments, a is 2 or 3.

[0162] In some embodiments, a is depicted in the compounds of Table 1, below.

[0163] In some embodiments, Ring C together with its R1Aand L5 substituent is

[0165] In some embodiments, Ring C together with its R1Aand Ls substituent is as depicted in the compounds of Table 1, below.

[0166] As defined generally above, Li is selected from a bond, -O-, -S-, -S(O)2-, -NR1-, -C(O)-, -C(O)NRJ-, -NRJC(O)-, -NR1C(O)NR1-, and –[C(R1a)(R1b)]1-2-.

[0167] In some embodiments, Li is a bond. In some embodiments, Li is -O-. In some embodiments, Li is -S-. In some embodiments, Li is -S(O)2-. In some embodiments, Li is -NR1-. In some embodiments, Li is -C(O)-. In some embodiments, Li is -C(O)NR1-. In some embodiments, L1is -NR1C(O)-. In some embodiments, Li is -NR1C(O)NR1-. In some embodiments, Li is -[C(Rla)(Rlb)]i-2-.

[0168] As defined generally above, L2 is selected from a bond, a substituted or unsubstituted alkenylene, -O-, -S-, -S(O)2-, -N= S(O)(CH3)-, -S(O)(CH3)=N-, -S(O)2NR1-, -NR1S(O)2-, -NR1-, -C(O)-, -C(O)NRJ-, -NRJC(O)-, -NR1C(O)NR1-, an optionally substituted C3-C6 cycloalkyl, an optionally substituted C3-Ce heterocycloalkyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and -[C(R2a)(R2b)]i-2-.

[0169] In some embodiments, L2 is a bond. In some embodiments, L2 is a substituted or unsubstituted alkenylene. In some embodiments, L2 is -O-. In some embodiments, L2 is -S-. In some embodiments, L2 is -S(O)2-. In some embodiments, L2 is -N= S(O)(CH3)-. In some embodiments, L2 is -S(O)(CH3)=N-. In some embodiments, L2 is -S(O)2NR1-. In some embodiments, L2is -NR1S(O)2-. In some embodiments, L2is -NR1-. In some embodiments, L2is -C(O)-. In some embodiments, L2is -C(O)NR1-. In some embodiments, L2is -NR1C(O)-. In some embodiments, L2is -NR1C(O)NR1-. In some embodiments, L2is an optionally substituted C3-C6 cycloalkyl. In some embodiments, L2is an optionally substituted C3-Ce heterocyclo alkyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, L2 is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, L2 is -[C(R2a)(R2b)]i-2-.

[0170] As defined generally above, L3is selected from a bond, a substituted or unsubstituted alkenylene, -O-, -S-, -S(O)2-, -N= S(O)(CH3)-, -S(O)(CH3)=N-, -S(O)2NR1-, -NR1S(O)2-, -NR1-, -C(O)-, -C(O)NRJ-, -NRJC(O)-, -NR1C(O)NR1-, an optionally substituted C3-C6 cycloalkyl, an optionally substituted C3-Ce heterocycloalkyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and -[C(R3a)(R3b)]i-2-.

[0171] In some embodiments, L3 is a bond. In some embodiments, L3 is a substituted or unsubstituted alkenylene. In some embodiments, L3 is -O-. In some embodiments, L3 is -S-. In some embodiments, L3 is -S(O)2-. In some embodiments, L3 is -N= S(O)(CH3)-. In some embodiments, L3 is -S(O)(CH3)=N-. In some embodiments, L3 is -S(O)2NR1-. In some embodiments, L3 is -NR1S(O)2-. In some embodiments, L3 is -NR1-. In some embodiments, L3 is -C(O)-. In some embodiments, L3is -C(O)NR1-. In some embodiments, L3 is -NR1C(O)-. In some embodiments, L3 is -NR1C(O)NR1-. In some embodiments, L3 is an optionally substituted C3-C6 cycloalkyl. In some embodiments, L3 is an optionally substituted C3-C6 heterocyclo alkyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, L3 is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, L3 is -[C(R3a)(R3b)]i-2-.

[0172] As defined generally above, L4 is selected from a bond, a substituted or unsubstituted alkenylene, -O-, -S-, -S(O)2-, -N= S(O)(CH3)-, -S(O)(CH3)=N-, -S(O)2NR1-, -NR1S(O)2-, -NR1-, -C(O)-, -C(O)NR1-, -NRJC(O)-, -NR1C(O)NR1-, an optionally substituted C3-C6 cycloalkyl, an optionally substituted C3-C6 heterocycloalkyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and -[C(R4a)(R4b)]i-2-.

[0173] In some embodiments, L4 is a bond. In some embodiments, L4 is a substituted or unsubstituted alkenylene. In some embodiments, L4 is -O-. In some embodiments, L4 is -S-. In some embodiments, L4 is -S(O)2-. In some embodiments, L4 is -N= S(O)(CH3)-. In some embodiments, L4 is -S(O)(CH3)=N-. In some embodiments, L4 is -S(O)2NR1-. In some embodiments, L4is -NR1S(O)2-. In some embodiments, L4is -NR1-. In some embodiments, L4 is -C(O)-. In some embodiments, L4 is -C(O)NR1-. In some embodiments, L4is -NR1C(O)-. In some embodiments, L4 is -NR1C(O)NR1-. In some embodiments, L4 is an optionally substituted C3-C6 cycloalkyl. In some embodiments, L4is an optionally substituted C3-C6 heterocyclo alkyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, L4 is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, L4 is -[C(R4a)(R4b)]i-2-.

[0174] As defined generally above, L5 is selected from a bond, -O-, -S-, -S(O)2-, -NR1-, -C(O)-, -C(O)NRJ-, -NRJC(O)-, -NR1C(O)NR1-, and –[C(R5a)(R5b)]1-2-.

[0175] In some embodiments, L5 is a bond. In some embodiments, L5 is -O-. In some embodiments, L5 is -S-. In some embodiments, L5 is -S(O)2-. In some embodiments, L5 is -NR1-. In some embodiments, L5 is -C(O)-. In some embodiments, L5is -C(O)NR1-. In some embodiments, L5is -NR1C(O)-. In some embodiments, L5 is -NR1C(O)NR1-. In some embodiments, L5 is -[C(Rla)(Rlb)]i-2-.

[0176] In some embodiments, Li is -CH2- or -O- and L5 is -CH2- or -O-. In some embodiments, Li is -O- and L5 is -CH2-. In some embodiments, Li is -CH2- and L5 is -O-. In some embodiments, Li is -O- and L5 is -O-.

[0177] In some embodiments, Li, L2, L3, L4, and L5 together formIn some embodiments, Li, L2, L3, L4, and L5 form a moiety as depicted in the compounds of Table 1, below.

[0179] As defined generally above, R3is -C(O)-Le, -S(O)2-L6, an optionally substituted C1-6(R6B)baliphatic, an optionally substituted C1-6 aliphatic substituted with(R6A)C; ANoptionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms(R6B)bindependently selected from nitrogen, oxygen, and sulfur, or(R6A)C.

[0180] In some embodiments, R3is -C(O)-Le. In some embodiments, R3is -S(O)2-Le. In some embodiments, R3is an optionally substituted C1-6 aliphatic. In some embodiments, R3is an(R6B)boptionally substituted Ci-6 aliphatic substituted with (R6A)C [nsome embodiments R3is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3isIn some embodiments, R3is (r6A)

[0182] In some embodiments, R3is as depicted in the compounds of Table 1, below.R8R8

[0183] As defined generally above, Lr, is

[0184] In some embodiments, Le isIn some embodiments, Le isR8R8some embodiments, Le isIn some embodiments, Le is. In some^^R9embodiments, Le isr8 r8In some embodiments, Le isIn some embodiments, VCk W9Le is. In some embodiments, Le isR8R8. In some embodiments, Le is

[0187] In some embodiments, Lr, is methyl.

[0195] In some embodiments, L6is as depicted in the compounds of Table 1, below.

[0196] As defined generally above, each Rla, Rlb, R2a, R2b, R3a, R3b, R4a, R4b, R5a, and R5b, are independently selected from the group consisting of hydrogen, halogen, hydroxyl, N(R1)2, C1-3 alkyl, -CN, C1-3 alkoxy, C0–3alkyl-C3-C6cycloalkyl, C0–3alkyl-C3-C6heterocycloalkyl, and hydroxy-Ci-3 alkyl, and halo-Ci-3 alkyl, orRlaand Rlb, R2aand R2b, R3aand R3b, R4aand R4b, or R5aand R5b, and the carbon atom to which they are attached may combine to form:a) a 3-7 membered saturated or partially unsaturated bivalent monocyclic carbocyclylene or 4-7 membered saturated or partially unsaturated bivalent heterocyclylene ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 nitrogen atoms in addition to the 1-4 heteroatoms) - substituted with y instances of RB, orb) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene orheterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) - substituted with y instances of RB, orRlaand R2a, Rlaand R3a, R2aand R3a, R2aand R4a, R3aand R4a, R3aand R5a, or R4aand R5a, and the atoms to which they are connected may combine to form:a) a 3-7 membered saturated or partially unsaturated bivalent monocyclic carbocyclylene or a 4-7 membered saturated or partially unsaturated bivalent heterocyclylene ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 nitrogen atoms in addition to the 1-4 heteroatoms) - substituted with y instances of RB, orb) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene or heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) - substituted with y instances of RB.

[0197] In some embodiments, each Rla, Rlb, R2a, R2b, R3a, R3b, R4a, R4b, R5a, and R5b, are independently selected from the group consisting of hydrogen, halogen, hydroxyl, N(R1)2, C1–3alkyl, –CN, C1–3alkoxy, C0–3alkylC3-C6cycloalkyl, C0–3alkylC3-C6heterocycloalkyl, and C1–3hydroxyalkyl, and C1–3haloalkyl.

[0198] In some embodiments, Rlais hydrogen. In some embodiments, Rlais halogen. In some embodiments, Rlais -CN. In some embodiments, Rlais N(R1)2. In some embodiments, Rlais hydroxyl. In some embodiments, Rlais C1-3 alkyl. In some embodiments, Rlais C1-3 alkoxy. In some embodiments, Rlais C0–3alkylC3-C6cycloalkyl. In some embodiments, Rlais C0–3alkylC3-C6heterocycloalkyl. In some embodiments, Rlais C1-3 hydroxyalkyl. In some embodiments, Rlais C1–3haloalkyl.

[0199] In some embodiments, Rlbis hydrogen. In some embodiments, Rlbis halogen. In some embodiments, Rlbis -CN. In some embodiments, Rlbis N(R1)2. In some embodiments, Rlbis hydroxyl. In some embodiments, Rlbis C1-3 alkyl. In some embodiments, Rlbis C1-3 alkoxy. In some embodiments, Rlbis C0–3alkylC3-C6cycloalkyl. In some embodiments, Rlbis C0–3alkylC3-C6heterocycloalkyl. In some embodiments, R1bis C1–3hydroxyalkyl. In some embodiments, R1bis C1–3haloalkyl.

[0200] In some embodiments, R2ais hydrogen. In some embodiments, R2ais halogen. In some embodiments, R2ais -CN. In some embodiments, R2ais N(R1)2. In some embodiments, R2aishydroxyl. In some embodiments, R2ais C1-3 alkyl. In some embodiments, R2ais C1-3 alkoxy. In some embodiments, R2ais C0–3alkylC3-C6cycloalkyl. In some embodiments, R2ais C0–3alkylC3-C6heterocycloalkyl. In some embodiments, R2ais C1-3 hydroxyalkyl. In some embodiments, R2ais C1–3haloalkyl.

[0201] In some embodiments, R2bis hydrogen. In some embodiments, R2bis halogen. In some embodiments, R2bis -CN. In some embodiments, R2bis N(R1)2. In some embodiments, R2bis hydroxyl. In some embodiments, R2bis C1-3 alkyl. In some embodiments, R2bis C1-3 alkoxy. In some embodiments, R2bis C0–3alkylC3-C6cycloalkyl. In some embodiments, R2bis C0–3alkylC3-C6heterocycloalkyl. In some embodiments, R2bis C1-3 hydroxyalkyl. In some embodiments, R2bis C1-3 haloalkyl.

[0202] In some embodiments, R3ais hydrogen. In some embodiments, R3ais halogen. In some embodiments, R5ais -CN. In some embodiments, R3ais N(R1)2. In some embodiments, R3ais hydroxyl. In some embodiments, R2ais C1-3 alkyl. In some embodiments, R3ais C1-3 alkoxy. In some embodiments, R3ais C0–3alkylC3-C6cycloalkyl. In some embodiments, R3ais C0–3alkylC3-C6heterocycloalkyl. In some embodiments, R3ais C1-3 hydroxyalkyl. In some embodiments, R3ais C1-3 haloalkyl.

[0203] In some embodiments, R3bis hydrogen. In some embodiments, R3bis halogen. In some embodiments, R3bis -CN. In some embodiments, R3bis N(R1)2. In some embodiments, R3bis hydroxyl. In some embodiments, R3bis C1-3 alkyl. In some embodiments, R3bis C1-3 alkoxy. In some embodiments, R3bis C0–3alkylC3-C6cycloalkyl. In some embodiments, R3bis C0–3alkylC3-C6heterocycloalkyl. In some embodiments, R3bis C1-3 hydroxyalkyl. In some embodiments, R3bis C1-3 haloalkyl.

[0204] In some embodiments, R4ais hydrogen. In some embodiments, R4ais halogen. In some embodiments, R4ais -CN. In some embodiments, R4ais N(R1)2. In some embodiments, R4ais hydroxyl. In some embodiments, R4ais C1-3 alkyl. In some embodiments, R4ais C1-3 alkoxy. In some embodiments, R4ais C0–3alkylC3-C6cycloalkyl. In some embodiments, R4ais C0–3alkylC3-C6heterocycloalkyl. In some embodiments, R4ais C1-3 hydroxyalkyl. In some embodiments, R4ais C1–3haloalkyl.

[0205] In some embodiments, R4bis hydrogen. In some embodiments, R4bis halogen. In some embodiments, R4bis -CN. In some embodiments, R4bis N(R1)2. In some embodiments, R4bis hydroxyl. In some embodiments, R4bis C1-3 alkyl. In some embodiments, R4bis C1-3 alkoxy. Insome embodiments, R4bis C0-3 alkylCa-Ce cycloalkyl. In some embodiments, R4bis C0-3 alkylCs-Ce heterocycloalkyl. In some embodiments, R4bis C1-3 hydroxyalkyl. In some embodiments, R4bis C1-3 haloalkyl.

[0206] In some embodiments, R5ais hydrogen. In some embodiments, R5ais halogen. In some embodiments, R5ais -CN. In some embodiments, R5ais N(R1)2. In some embodiments, R5ais hydroxyl. In some embodiments, R5ais C1-3 alkyl. In some embodiments, R5ais C1-3 alkoxy. In some embodiments, R5ais C0-3 alkylC3-C6 cycloalkyl. In some embodiments, R5ais C0-3 alkylCs-Ce heterocycloalkyl. In some embodiments, R5ais C1-3 hydroxyalkyl. In some embodiments, R5ais C1-3 haloalkyl.

[0207] In some embodiments, R5bis hydrogen. In some embodiments, R5bis halogen. In some embodiments, R5bis -CN. In some embodiments, R5bis N(R1)2. In some embodiments, R5bis hydroxyl. In some embodiments, R5bis C1-3 alkyl. In some embodiments, R5bis C1-3 alkoxy. In some embodiments, R5bis C0-3 alkylC3-C6 cycloalkyl. In some embodiments, R5bis C0-3 alkylC’3-Ce heterocycloalkyl. In some embodiments, R5bis C1-3 hydroxyalkyl. In some embodiments, R5bis C1-3 haloalkyl.

[0208] In some embodiments, each Rla, Rlb, R2a, R2b, R3a, R3b, R4a, R4b, R5a, and R5b, are independently as depicted in the compounds of Table 1, below.

[0209] As generally defined above, each R is independently hydrogen, -C(O)N(CH3)2, -C(O)2CH3, -C(O)2C(CH3)3, -C(O)2CH(CH3)2, -S(O)2CH3, an optionally substituted C1-6 aliphatic group, an optionally substituted cyclic group, or an optionally substituted C1-6 alkyl-cyclic group, wherein the cyclic group is selected from:• phenyl;• an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring;• an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• an optionally substituted 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• an optionally substituted 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• and optionally substituted 6-11 membered saturated or partially unsaturated bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and / ortwo R groups on the same atom are taken together with the same atom to form a cyclic group selected from:• an optionally substituted 4-7 membered saturated or partially unsaturated carbocyclyl;• an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and• an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the optionally substituted R moiety is substituted with 0, 1, 2, 3, or 4 RSub; each RSubis independently selected from Ci-6 aliphatic group substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -N(RN)2, and -O RN; halogen; -CN; - NO2; -ORN; -SRN; -N(RN)2; -S(O)2RN; -S(O)2N(RN)2; -S(O)RN; -S(O)N(RN)2; -C(O)RN; -C(O)ORN; -C(O)N(RN)2; -C(O)N(RN)ORN; -OC(O)RN; -OC(O)N(RN)2; -N(RN)C(O)ORN; -N(RN)C(O)RN; -N(RN)C(O)N(RN)2; -N(RN)C(NRN)N(RN)2; -N(RN)S(O)2N(RN)2; and -N(RN)S(O)2RN; and each RNis independently selected from H and C1-3 alkyl.

[0210] In some embodiments, each R is independently hydrogen, or an optionally substituted group selected from Ci-6 aliphatic; phenyl; naphthyl; a 3-7 membered saturated or partiallyunsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 6-11 membered saturated or partially unsaturated bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same atom are optionally taken together with the atom to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0211] In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted Ci-6 aliphatic. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted naphthyl. In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 6-10 membered saturated or partiallyunsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 6-11 membered saturated or partially unsaturated bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same atom are taken together with the atom to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, two R groups on the same atom are taken together with the atom to form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same atom are optionally taken together with the atom to form an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0212] In some embodiments, each R is as depicted in the compounds of Table 1, below.

[0213] In some embodiments, the compound of formula I is a compound of formulae II-a, II-b, II-c, II-d, or II-e:li eor a pharmaceutically acceptable salt thereof, wherein:Xi and X2 are independently selected from CH, N, CF, CC1, CCH3; andRing C is a 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0214] In some embodiments, the present invention provides a compound formula I is a compound of formulae H-a, Il-b, II-c, H-d, or Il-e or a pharmaceutically acceptable salt thereof, wherein:Xi and X2 and are independently selected from N, CF, CO, CCH> and CH; andRing C is a 6-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0215] In some embodiments, the present invention provides a compound formula I is a compound of formulae H-a, Il-b, II-c, Il-d, or Il-e or a pharmaceutically acceptable salt thereof, wherein:Xi and X2 and are independently selected from N, CF, CO, CCH3 and CH; andRing C is an 8-10 membered bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0216] In some embodiments, the present invention provides a compound formula I is a compound of formulae H-a, Il-b, II-c, H-d, or Il-e, or a pharmaceutically acceptable salt thereof, wherein: Xi and X2 and are independently selected from N, CF, CC1, CCH? and CH; andRing C is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0217] In some embodiments, the compound of formula I is a compound of formulae ILa, Il-b, II-c, Il-d, or Il-e:or a pharmaceutically acceptable salt thereof, wherein:Xi and X2 are independently selected from CH, N, CF, CC1, CCH3.

[0218] In some embodiments, the compound of formula I is a compound of formulae Ill-a, Ill-b, III-c, Ill-d, or Ill-e:Ill-a Ill-bor a pharmaceutically acceptable salt thereof, wherein:X1and X2are independently selected from CH, N, CF, CCl, and CCH3.

[0219] In some embodiments, the compound of formula I is a compound of formulae IV-a, IV-b, IV-c, IV-d, or VI-e:or a pharmaceutically acceptable salt thereof, wherein:Xi and X2 are independently selected from CH, N, CF, CC1, CCH3; andL6is selected from the group consisting of

[0220] In some embodiments, the compound of formula I is a compound of formulae V-a, V-b, V-c, V-d, or V-e:V-eor a pharmaceutically acceptable salt thereof, wherein:X1and X2are independently selected from CH, N, CF, CCl, and CCH3.

[0221] In some embodiments, the compound of formula I is a compound of formulae Vl-a or VI-b:or a pharmaceutically acceptable salt thereof, wherein:L3 is independently selected from CH2 and CF2.

[0222] In some embodiments, the compound of formula I is a compound of formulae VH-a, VII-b, VII-c, VH-d, or VH-e:VH-eor a pharmaceutically acceptable salt thereof, wherein:L3 is independently selected from CH2 and CHCH3; and L4 is independently selected from CH2 and CHCH3.

[0223] In some embodiments, the compound of formula I is a compound of formulae VH-a or VH-b:or a pharmaceutically acceptable salt thereof, wherein:Ls is independently selected from CH2 and CHCH3; and L4 is independently selected from CH2 and CHCH3.

[0224] In some embodiments, the compound of formula I is a compound of formulae VIII-a, or VIII-b:VIII-a VIII-bor a pharmaceutically acceptable salt thereof, wherein:L3 is independently selected from CH2 and CHCH3; and L4 is independently selected from CH2 and CHCH3.

[0225] In some embodiments, the compound of formula I is a compound of formulae IX-a or IX-b:IX-a IX-bor a pharmaceutically acceptable salt thereof, wherein:L3 is independently selected from CH2 and CHCH3; and L4 is independently selected from CH2 and CHCH3.

[0226] In some embodiments, the compound of formula X is a compound of formulae X-a, X-b:X-a X-bor a pharmaceutically acceptable salt thereof, wherein:Li is selected from a bond, O, S and CH2; L5 is selected from a bond, O, S and CH2; andR10is independently selected from a H, -S-C1-3 alkyl, -CH2S-C1-3 alkyl.

[0227] Exemplary compounds of the invention are set forth in Table 1, or a pharmaceutically acceptable salt thereof. Table 1 identifies compounds by their IUPAC name and Table 2 lists the same compounds and shows their chemical structure. The chemical names in the present application are generated from the corresponding structures using either CHEMDRAW, or CHEMAXON. In some instances, chemical names generated from the structures may give a different structure when using the “Convert Name to Structure” function in CHEMDRAW. In the event of any discrepancy between Table 1’s name for a compound and Table 2’s structure for that same compound, Table 2’s compound structures will dominate and identify the compound corresponding to each respective compound number (I-#) in Table 1.Table 1. Exemplary CompoundsI-# IUPAC name(1 S,2R)-N- { 3-methyl-7,l 0-dioxa-3,4, 15,16- 1-1 tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl } -2-(5-methylpyridin-2-yl)cyclopropane- 1 -carboxamide(1 S,2R)-2- [5-(difluoromethyl)pyridin-2-yl]-N- { 3-methyl-7, 11 -dioxa-3,4, 16,17- 1-2 tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca-l(12),2(6),4,13,15,18-hexaen- 15 -yl } cyclopropane- 1 -carboxamideN- { 3-methyl-7, 10-dioxa-3,4, 15,16- 1-3 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen-14-yl } cyclopropanecarboxamide(lS,2R)-N-{3-methyl-7,ll-dioxa-3,4,16,17- -4 tetraazatetracyclo [ 10.7.0.0A{ 2, 6 }.0A{ 13, 17 } ]nonadeca- 1 ( 12),2(6),4, 13, 15, 18-hexaen- 15-yl}-2-(5-methylpyridin-2-yl)cyclopropane-l-carboxamide(IS,2R)-N-[(9R)-3,9-dimethyl-7, 10-dioxa-3,4, 15,16- -5 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl]-2-(5-methylpyridin-2-yl)cyclopropane-l -carboxamide(lS,2R)-N-[(8R)-3,8-dimethyl-7,10-dioxa-3,4,15,16- -6 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl]-2-(5-methylpyridin-2-yl)cyclopropane-l-carboxamide(IS,2R)-2- [5-(azetidin- 1 -yl)pyridin-2-yl]-N- { 3-methyl-7, 10-dioxa-3,4, 15,16- -7 tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl } cyclopropane- 1 -carboxamide( 1 S,2R)-2-(5 -fluoropyridin-2-yl)-N- { 3-methyl-7, 10-dioxa-3,4,15,16- -8 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl } cyclopropane- 1 -carboxamide( 1 S,2R)-N- { 3-methyl-7, 10-dioxa-3,4, 15,16- -9 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl } -2-(pyridin-2-yl)cyclopropane- 1 -carboxamideN-(2,6-dimethylpyrimidin-4-yl)-3-methyl-7,l 0-dioxa-3,4,l 5,16- -10 tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-amine3-methyl-N-(6-methylpyridazin-3-yl)-7,10-dioxa-3,4,15,16- -11 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14- amine3-methyl- 1 - { 3-methyl-7, 10-dioxa-3,4, 15,16- -12 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl} urea(lS,2R)-N-[(9S)-3,9-dimethyl-7,10-dioxa-3,4,15,16- -13 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl]-2-(5-methylpyridin-2-yl)cyclopropane-l -carboxamide(lS,2R)-N-[(8S)-3,8-dimethyl-7,10-dioxa-3,4,15,16- -14 tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl]-2-(5-methylpyridin-2-yl)cyclopropane-l-carboxamide(1 S,2R)-N- { 3-methyl- 10-oxa-3,4, 15,16- -15 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl } -2-(5-methylpyridin-2-yl)cyclopropane- 1 -carboxamide( 1 S,2R)-2-(4-methoxy-5 -methylpyridin-2-yl)-N- { 3-methyl-7, 10-dioxa-3,4, 15,16- -16 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl } cyclopropane- 1 -carboxamide(lS,2R)-2-{imidazo[l,2-b]pyridazin-2-yl}-N-{3-methyl-7,10-dioxa-3,4,15,16- -17 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen-14-yl } cyclopropane- 1 -carboxamide(1 S,2R)-2-(4,5 -dimethylpyridin-2-yl)-N- { 3-methyl-7, 10-dioxa-3,4, 15,16- -18 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl } cyclopropane- 1 -carboxamide( 1 S,2R)-N- { 9-hydroxy-3,9-dimethyl-7, 11 -dioxa-3,4,16,17- -19 tetraazatetracyclo[10.7.0.0^{2,6}.0^{13,17}]nonadeca-1(12),2(6),4,13,15,18-hexaen-15-yl}-2-(5-methylpyridin-2-yl)cyclopropane-1-carboxamide(1S,2R)-2-{5H,6H,8H-imidazo[2,1-c][1,4]oxazin-2-yl}-N-{3-methyl-7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0^{2,6}.0^{12,16}]octadeca-1(11),2(6),4,12,14,17- hexaen- 14-yl } cyclopropane- 1 -carboxamide(IS,2R)-N- { 4-methyl-8,l 1 -dioxa-5,16,17- -21 triazatetracyclo[10.7.0.0A{2,7}.0A{ 13,17}]nonadeca-l(12),2(7),3,5,13,15,18-heptaen- 15-yl}-2-(5-methylpyridin-2-yl)cyclopropane-l-carboxamide(lS,2R)-N-[3-(difluoromethyl)-7,10-dioxa-3,4,15,16,18- -22 pentaazatetracyclo[9.7.0.0A{2,6(.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl]-2-(5-methylpyridin-2-yl)cyclopropane-l -carboxamide( 1 S,2R)-2-( 1 -cyclopropyl- 1 H- 1,2,3-triazol-4-yl)-N- { 3-methyl-7, 10-dioxa-3,4, 15,16- -23 tetraazatetracyclo[9.7.0.0A{2,6(.0A{12,16(]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl } cyclopropane- 1 -carboxamide(1 S,2R)-2-(3-hydroxy-4-methylpyridin-2-yl)-N-{3-methyl-7,10-dioxa-3,4,15,16- -24 tetraazatetracyclo [9.7.0.0A{ 2,6 },0A{ 12, 16 } ]octadeca- 1(11), 2(6), 4, 12, 14, 17 -hexaen- 14-yl } cyclopropane- 1 -carboxamide(IS,2R)-2- [5-(difluoromethyl)pyridin-2-yl]-N- { 3-methyl-7, 10-dioxa-3,4, 15,16- -25 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl } cyclopropane- 1 -carboxamide( 1 S,2R)-N- { 3-methyl-7, 10-dioxa-3,4, 15,16- -26 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl } -2-(4-methylpyridin-2-yl)cyclopropane- 1 -carboxamide( 1 S,2R)-2-(5-fluoro-4-methylpyridin-2-yl)-N- { 3-methyl-7, 10-dioxa-3,4, 15,16- -27 tetraazatetracyclo[9.7.0.0A{2,6(.0A{12,16(]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl (cyclopropane- 1 -carboxamide(lS,2R)-2-{imidazo[l,2-a]pyridin-2-yl(-N-{3-methyl-7,10-dioxa-3,4,15,16- -28 tetraazatetracyclo[9.7.0.0A{2,6(.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl } cyclopropane- 1 -carboxamide(1 S,2R)-N- { 3-methyl-7,l 0-dioxa-3,4, 15,16,18- -29 pentaazatetracyclo[9.7.0.0A{2,6}.0A{12,16(]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl } -2-(5-methylpyridin-2-yl)cyclopropane- 1 -carboxamide( 1 S,2R)-2-(2-cyclopropyl-2H- 1,2,3,4-tetrazol-5-yl)-N- { 3-methyl-7, 10-dioxa- -30 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6).0A{12,16(]octadeca-l(ll),2(6),4,12,14,17- hexaen- 14-yl } cyclopropane- 1 -carboxamide2-(5-methyl-2-oxo- 1,2-dihydropyrimidin- 1 -yl)-N- { 3-methyl-7, 10-dioxa-3,4, 15,16- -31 tetraazatetracyclo[9.7.0.0A{2,6(.0A{12,16(]octadeca-l(ll),2(6),4,12,14,17-hexaen-14-yl (acetamideN- { 3-methyl-7, 10-dioxa-3,4, 15,16- -32 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl } -2- [(5 -methylpyridin-2-yl)oxy ]acetamide3-{3-methyl-7,10-dioxa-3,4,15,16- -33 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl } - 1 - [(5 -methylpyridin-2-yl)methyl]urea3-{3-methyl-7,10-dioxa-3,4,15,16- -34 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl } - 1 - [(5 -methylpyrimidin-2-yl)methyl]urea2-(5-methyl-2-oxo- 1,2-dihydropyridin- 1 -yl)-N- { 3-methyl-7, 10-dioxa-3,4, 15,16- -35 tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl} acetamiderel- 3 - [( 1 R,2S)-2-methoxycyclobutyl]- 1 - { 3-methyl-7, 10-dioxa-3,4, 15,16- -36 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl}urea (stereoisomer 1)rel-3- [( 1 R,2S)-2-methoxycyclobutyl]- 1 - { 3-methyl-7, 10-dioxa-3,4, 15,16- -37 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl}urea (stereoisomer 2)(1 S,2R)-2-[5-(fluoromethyl)pyridin-2-yl]-N-{3-methyl-7,10-dioxa-3,4,15,16- -38 tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl } cyclopropane- 1 -carboxamide(5 -methylpyridin-2-yl)methyl N- { 3-methyl-7, 10-dioxa-3,4, 15,16- -39 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl (carbamate(IS,2R)-N- { 3-methyl-7, 10-dioxa-3,4, 12,15,18- -40 pentaazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,13,15,17-hexaen- 14-yl }-2-(5-methylpyridin-2-yl)cyclopropane-l -carboxamide(lS,2R)-N-{3,7-dimethyl-8-oxo-10-oxa-3,4,7,15,16- -41 pentaazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll), 2(6), 4,12,14, 17-hexaen- 14-yl }-2-(5-methylpyridin-2-yl)cyclopropane-l -carboxamide(lS,2R)-N-[(9R*)-9-hydroxy-3,9-dimethyl-7,ll-dioxa-3,4,16,17- -42 tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca-l(12),2(6),4,13,15,18-hexaen- 15-yl]-2-(5-methylpyridin-2-yl)cyclopropane-l-carboxamide (stereoisomer 1) (lS,2R)-N-[(9R*)-9-hydroxy-3,9-dimethyl-7,ll-dioxa-3,4,16,17- -43 tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca-l(12),2(6),4,13,15,18-hexaen- 15-yl]-2-(5-methylpyridin-2-yl)cyclopropane-l-carboxamide (stereoisomer 2) N- { 3-methyl-7, 10-dioxa-3,4, 15,16- -44 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl}-2-[(5-methylpyrimidin-2-yl)oxy]acetamide(1 S,2R)-N-[3-(difluoromethyl)-7, 10-dioxa-3,4, 12,15,18- -45 pentaazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,13,15,17-hexaen-14-yl]-2-(5-methylpyridin-2-yl)cyclopropane-l-carboxamide(lS,2R)-N-[(8R*)-8-(2-hydroxypropan-2-yl)-3-methyl-7,10-dioxa-3,4,15,16- -46 tetraazatetracyclo[9.7.0.0A{2,6(.0A{12,16(]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl]-2-(5-methylpyridin-2-yl)cyclopropane-l-carboxamide (stereoisomer 1) (lS,2R)-N-[(8R*)-8-(2-hydroxypropan-2-yl)-3-methyl-7,10-dioxa-3,4,15,16- -47 tetraazatetracyclo[9.7.0.0A{2,6(.0A{12,16(]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl]-2-(5-methylpyridin-2-yl)cyclopropane-l -carboxamide (stereoisomer 2) ( 1 S,2R)-N- { 3-methyl- 10-oxa-4,6, 15,16- -48 tetraazatetracyclo[9.7.0.0A{2,6(.0A{12,16(]octadeca-l(ll),2,4,12,14,17-hexaen-14- yl }-2-(5-methylpyridin-2-yl)cyclopropane- 1 -carboxamide(lS,2R)-N-{3'-methyl-7', H'-dioxa-3',4',16',17'-tetraazaspiro[oxetane-3,9'- -49 tetracyclo[10.7.0.0A{2,6}.0A{ 13,17}]nonadecane]-l'(12'),2'(6'),4',13',15',18'-hexaen- 15'-yl}-2-(5-methylpyridin-2-yl)cyclopropane-l -carboxamide( 1 S,2R)-N- { 3-methyl- 10-oxa-5,6, 15,16- -50 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2,4,12,14,17-hexaen-14- yl } -2-(5 -methylpyridin-2-yl)cyclopropane- 1 -carboxamide( 1 S,2R)-N- { 3-methyl- 10-oxa-3,4, 15,16- -51 tetraazatetracyclo[9.7.0.0A{2,6(.0A{12,16(]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl } -2-(5-methylpyrimidin-2-yl)cyclopropane- 1 -carboxamide2-(5-methoxy-l H-pyrazol-1 -yl)-N-{3-methyl-7,l 0-dioxa-3,4,l 5,16- -52 tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl (acetamide(lS,2R)-2-{2-methyl-2H-pyrazolo[3,4-c]pyridin-5-yl(-N-{3-methyl-7,10-dioxa- -53 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- hexaen- 14-yl } cyclopropane- 1 -carboxamide(IS,2R)-N- { 3-methyl-7, 11 -dioxa-3,4, 16,17- -54 tetraazatetracyclo[10.7.0.0^{2,6}.0^{13,17}]nonadeca-1(12),2(6),4,13,15,18-hexaen-15-yl}-2-(5-methylpyrimidin-2-yl)cyclopropane-1-carboxamide(1S,2R)-N-{3'-methyl-7',11'-dioxa-3',4',16',17'-tetraazaspiro[cyclopropane-1,9'- -55 tetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadecane]-l'(12'),2'(6'),4',13',15',18'-hexaen- 15'-yl}-2-(5-methylpyrimidin-2-yl)cyclopropane-l -carboxamide(lS,2R)-2-(5-methylpyridin-2-yl)-N-[(ls,18s)-13-methyl-2,17-dioxa-7,8,13,14- -56 tetraazapentacyclo[16.1.1.0A{3,ll(.0A{4,8}.0A{12,16}]icosa-3(ll),4,6,9,12(16),14- hexaen-6-yl]cyclopropane- 1 -carboxamide(1 S,2R)-N- { 3-methyl-7,l 0-dioxa-3,4, 15,16- -57 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl } -2-[5-(2H3)methylpyridin-2-yl]cyclopropane- 1 -carboxamide( 1 S,2R)-N- { 3-methyl-7, 10-dioxa-3,4, 15,16- -58 tetraazatetracyclo[9.7.0.0A{2,6(.0A{12,16(]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl(-2-[5-(trifluoromethyl)pyridin-2-yl]cyclopropane-l-carboxamide2-(3-methoxy- 1 H-pyrazol- 1 -yl)-N- { 3-methyl-7, 10-dioxa-3,4, 15,16- -59 tetraazatetracyclo[9.7.0.0A{2,6(.0A{12,16(]octadeca-l(ll),2(6),4,12,14,17-hexaen-14-yl (acetamide(1 S,2R)-N- { 3-methyl-7,l 0-dioxa-3,4, 15,16- -60 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl } -2-(5-methylpyrimidin-2-yl)cyclopropane- 1 -carboxamide3-{3-methyl-7,10-dioxa-3,4,15,16- -61 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl } - 1 -[( 1 R)- 1 -(5-methylpyridin-2-yl)ethyl]urea( 1 S,2R)-2-(5- { bicyclo[ 1.1.1 ]pentan- 1 -yl }pyrimidin-2-yl)-N- { 3-methyl-7, 10-dioxa- -62 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- hexaen- 14-yl } cyclopropane- 1 -carboxamide(lS,2R)-N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- -63 tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl] -2-(5 -methylpyrimidin-2-yl)cyclopropane- 1 -carboxamide(IS,2R)-N-[(8R)-3,8-dimethyl-7, 10-dioxa-3,4, 15,16- -64 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl] -2-(5 -methylpyrimidin-2-yl)cyclopropane- 1 -carboxamide( 1 S,2R)-2-(5-cyclopropylpyrimidin-2-yl)-N- { 3-methyl-7, 10-dioxa-3,4, 15,16- -65 tetraazatetracyclo [9.7.0.0A{ 2,6 }.0A{ 12, 16 } ]octadeca- 1(11), 2(6), 4, 12, 14, 17 -hexaen- 14-yl } cyclopropane- 1 -carboxamide(1 S,2R)-N-{3,9-dimethyl-l 0-oxa-3,4,l 5,16- -66 tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl } -2-(5-methylpyrimidin-2-yl)cyclopropane- 1 -carboxamide(IS,2R)-2-(4-fluoro-5 -methylpyridin-2-yl)-N- { 3-methyl-7, 10-dioxa-3,4, 15,16- -67 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16]]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl } cyclopropane- 1 -carboxamiderel-(3R)-4,4-difluoro-3-(4-methyl- 1 H-pyrazol- 1 -yl)-N- { 3-methyl-7, 10-dioxa- -68 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16]]octadeca-l(ll),2(6),4,12,14,17- hexaen-14-yl}butanamide (stereoisomer 1)rel-(3R)-4,4-difluoro-3-(4-methyl-lH-pyrazol-l-yl)-N-{3-methyl-7,10-dioxa- -69 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- hexaen- 14-yl }butanamide (stereoisomer 2)(1 S,2R)-N- { 3-methyl-7,l 0-dioxa-3,4, 15,16- -70 tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl } -2-[5-(trifluoromethyl)pyrimidin-2-yl]cyclopropane- 1 -carboxamide (lS,2R)-2-[5-(difluoromethyl)pyridin-2-yl]-N-[(9R)-3,9-dimethyl-7,10-dioxa- -71 3,4, 15, 16-tetraazatetracyclo[9.7.0.0A{ 2, 6 }.0A{ 12, 16 } ]octadeca- 1 (11), 2(6), 4, 12, 14,17- hexaen- 14-yl] cyclopropane- 1 -carboxamide(lS,2R)-2-(4,5-dimethylpyrimidin-2-yl)-N-{3-methyl-7,10-dioxa-3,4,15,16- -72 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl } cyclopropane- 1 -carboxamide(lS,2R)-N-[(10R)-3,10-dimethyl-7,l l-dioxa-3,4,16,17- -73 tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca-l(12),2(6),4,13,15,18-hexaen-15-yl]-2-(5 -methylpyrimidin-2-yl)cyclopropane- 1 -carboxamide(lS,2R)-N-[(8R)-3,8-dimethyl-7,ll-dioxa-3,4,16,17- -74 tetraazatetracyclo [ 10.7.0.0A{ 2, 6 }.0A{ 13, 17 } ]nonadeca- 1 ( 12),2(6),4, 13, 15, 18-hexaen- 15-yl]-2-(5 -methylpyrimidin-2-yl)cyclopropane- 1 -carboxamide( 1 S,2R)-2- [5 -(difluoromethyl)pyridin-2-yl]-N- { 3-methyl- 10-oxa-3,4, 15,16- -75 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl } cyclopropane- 1 -carboxamide(lS,2R)-N-{9,9-difluoro-3-methyl-7,ll-dioxa-3,4,16,17- -76 tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca-l(12),2(6),4,13,15,18-hexaen- 15 -yl } -2-(5 -methylpyrimidin-2-yl)cyclopropane- 1 -carboxamide(lS,2R)-2-(5-cyclopropylpyrimidin-2-yl)-N-[(10R)-3,10-dimethyl-7,ll-dioxa- -77 3,4,16,17-tetraazatetracyclo[10.7.0.0A{2,6}.0A{ 13,17}]nonadeca- 1 (12), 2(6), 4, 13,15,18-hexaen- 15 -yl]cyclopropane- 1 -carboxamideN- { 3-methyl-7, 10-dioxa-3,4, 15,16- -78 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl } methanesulfonamide(lS,2R)-2-(5-cyclopropylpyrimidin-2-yl)-N-[(8R)-3,8-dimethyl-7,ll-dioxa-3,4,16,17- -79 tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca-l(12),2(6),4,13,15,18-hexaen- 15 -yl]cyclopropane- 1 -carboxamideN-{3-methyl-7,l 0-dioxa-3,4,l 5,16- -80 tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl } cyclopropanesulfonamide(IS,2R)-2- [5-(fluoromethyl)pyridin-2-yl]-N- { 3-methyl- 10-oxa-3,4, 15,16- -81 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl } cyclopropane- 1 -carboxamide(1S,2R)-2-[5-(fluoromethyl)pyridin-2-yl]-N-{3-methyl-7,11-dioxa-3,4,16,17- -82 tetraazatetracyclo[10.7.0.0^{2,6}.0^{13,17}]nonadeca-1(12),2(6),4,13,15,18-hexaen-15-yl}cyclopropane-1-carboxamide3-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- -83 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl ]- 1 -[(5-methylpyridin-2-yl)methyl]urea(1 S,2R)-N- { 18-fluoro-3-methyl-7, 10-dioxa-3,4, 15,16- -84 tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl } -2-(5-methylpyridin-2-yl)cyclopropane- 1 -carboxamide3-{3-methyl-10-oxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- -851(11), 2(6), 4, 12, 14, 17 -hexaen- 14-yl } - 1 - [(5 -methy lpyridin-2-yl)methyl]urea (lS,2R)-N-[(9R*)-3,9-dimethyl-10-oxa-3,4,15,16- -86 tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl] -2-(5 -methylpyrimidin-2-yl)cyclopropane- 1 -carboxamide (stereoisomer 1 ) (1 S,2R)-N-[(9R*)-3,9-dimethyl- 10-oxa-3,4, 15,16- -87 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen-14-yl]-2-(5-methylpyrimidin-2-yl)cyclopropane-l -carboxamide (stereoisomer 2)(lS,2R)-N-[3-(difluoromethyl)-7,10-dioxa-3,4,15,16- -88 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl]-2-(5-methylpyridin-2-yl)cyclopropane-l-carboxamide(lS,2R)-N-{3-methyl-8,ll-dioxa-3,4,16,17- -89 tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca-l(12),2(6),4,13,15,18-hexaen- 15-yl } -2-(5-methylpyridin-2-yl)cyclopropane- 1 -carboxamide( 1 S,2R)-N- { 3-methyl-9-oxa-3,4, 14,15- -90 tetraazatetracyclo[8.7.0.0A{ 2,6}.0A{ 11,15 }]heptadeca- 1(10), 2(6), 4, 11, 13,16-hexaen- 13-yl } -2-(5-methylpyridin-2-yl)cyclopropane- 1 -carboxamide3-{3-methyl-7,ll-dioxa-3,4,16,17- -91 tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca-l(12),2(6),4,13,15,18-hexaen- 15 -yl } - 1 - [(5 -methylpyridin-2-yl)methyl]urea(lS,2R)-2-(5-cyclopropylpyrimidin-2-yl)-N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- -92 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl]cyclopropane- 1 -carboxamide(lS,2R)-N-[(8R)-8-ethyl-3-methyl-7,10-dioxa-3,4,15,16- -93 tetraazatetracyclo [9.7.0.0A{ 2,6 }.0A{ 12, 16 } ]octadeca- 1(11), 2(6), 4, 12, 14, 17 -hexaen- 14-y 1] -2-(5 -methylpyrimidin-2-yl)cyclopropane- 1 -carboxamide(1 S,2R)-N-[(9R)-9-ethyl-3-methyl-7,l 0-dioxa-3,4,l 5,16- -94 tetraazatetracyclo [9.7.0.0A{ 2,6 },0A{ 12, 16 } ]octadeca- 1(11), 2(6), 4, 12, 14, 17 -hexaen- 14-yl] -2-(5 -methylpyrimidin-2-yl)cyclopropane- 1 -carboxamiderel- 1 -[( 1 R)- 1 -(5-cyclopropylpyridin-2-yl)ethyl]-3- { 3-methyl-7, 10-dioxa-3,4, 15,16- -95 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl}urea (stereoisomer 1)rel- 1 -[( 1 R)- 1 -(5-cyclopropylpyridin-2-yl)ethyl]-3- { 3-methyl-7, 10-dioxa-3,4, 15,16- -96 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl}urea (stereoisomer 2)( 1 S,2R)-2-(4,5-dimethylpyrimidin-2-yl)-N- { 3-methyl- 10-oxa-3,4, 15,16- -97 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl (cyclopropane- 1 -carboxamide1 - { 3-methyl-7, 10-dioxa- 3,4, 15,16- -98 tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl } -3- [ 1 -(5 -methylpyridin-2-yl)cyclopropyl]urea1 - { [5-(difluoromethyl)pyridin-2-yl]methyl } -3- { 3-methyl-7, 10-dioxa-3,4, 15,16- -99 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl} urea(lS,2R)-2-(5-cyclopropylpyrimidin-2-yl)-N-[(8R)-3,8-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 0014-yl]cyclopropane- 1 -carboxamide(lS,2R)-N-[(9R,13R)-3,10-dimethyl-7,14-dioxa-3,4,10,19,20- I- pentaazapentacyclo[13.7.0.0A{2,6}.0A{9,13}.0A{16,20}]docosa- 01 1 (15), 2(6), 4, 16, 18,21 -hexaen- 18-yl] -2- (5 -methylpyridin-2-yl)cyclopropane- 1 - carboxamide(1 S,2R)-N-[(8R, 12R)-3,11 -dimethyl-7, 14-dioxa-3,4,l 1,19,20- I- pentaazapentacyclo[13.7.0.0A{2,6}.0A{8,12}.0A{ 16,20}]docosa- 02 1 (15), 2(6), 4, 16,18,21 -hexaen- 18-yl] -2- (5 -methylpyridin-2-yl)cyclopropane- 1 - carboxamide(lS,2R)-N-[(8R)-3,8-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 0314-yl]-2-(4,5-dimethylpyrimidin-2-yl)cyclopropane-l -carboxamide(1 S,2R)-N-[(9R)-3,9-dimethyl-7,l 0-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 0414-yl] -2- [5 -(fluoromethyl)pyridin-2-yl]cyclopropane- 1 -carboxamide( 1 S,2R)-2- [5-(difluoromethyl)pyrimidin-2-yl]-N- [(9R)-3,9-dimethyl-7, 10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 05hexaen- 14-yl]cyclopropane- 1 -carboxamide(lS,2R)-2-(4,5-dimethylpyrimidin-2-yl)-N-{3-methyl-7,ll-dioxa-3,4,16,17- I- tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca-l(12),2(6),4,13,15,18-hexaen- 0615 -yl } cyclopropane- 1 -carboxamide(lS,2R)-2-[5-(difluoromethyl)pyrimidin-2-yl]-N-{3-methyl-7,ll-dioxa-3,4, 16,17- I- tetraazatetracyclo[10.7.0.0A{ 2,6}.0A{ 13,17 }]nonadeca- 1(12), 2(6), 4, 13, 15,18-hexaen- 0715 -yl } cyclopropane- 1 -carboxamide(IS,2R)-N-[(9R)-3,9-dimethyl-7, 10-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l (11 ), 2(6), 4,12,14,17 -hexaen - 0814-yl]-2-(4,5-dimethylpyrimidin-2-yl)cyclopropane-l-carboxamide(lS,2R)-2-(5-cyclopropylpyrimidin-2-yl)-N-{3-methyl-7,ll-dioxa-3,4,16,17- I- tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca-l(12),2(6),4,13,15,18-hexaen- 0915 -yl } cyclopropane- 1 -carboxamide(1 S,2R)-2-(5-methoxypyrazin-2-yl)-N-{3-methyl-7,l l-dioxa-3,4,16,17- I- tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca-l(12),2(6),4,13,15,18-hexaen- 1015 -yl } cyclopropane- 1 -carboxamide(IS,2R)-2-(4,6-dimethylpyrimidin-2-yl)-N- { 3-methyl-7, 11 -dioxa-3,4, 16,17- I- tetraazatetracyclo[ 10.7.0.0A{ 2,6}.0A{ 13,17 }]nonadeca- 1(12), 2(6), 4, 13, 15,18-hexaen- 1115 -yl } cyclopropane- 1 -carboxamide(1S,2R)-N-{3-methyl-7,11-dioxa-3,4,16,17- I- tetraazatetracyclo[10.7.0.0^{2,6}.0^{13,17}]nonadeca-1(12),2(6),4,13,15,18-hexaen- 1215 -yl } -2-(5-methylpyrazin-2-yl)cyclopropane- 1 -carboxamide(lS,2R)-2-(5-cyclopropylpyrimidin-2-yl)-N-[(9R*)-3,9-dimethyl-10-oxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 1314-yl]cyclopropane-l -carboxamide (stereoisomer 1)( 1 S,2R)-2-(5 -cyclopropylpyrimidin-2-yl)-N- [(9R*)-3,9-dimethyl- 10-oxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 1414-yl]cyclopropane-l -carboxamide (stereoisomer 2)(lS,2R)-2-(5-methylpyrimidin-2-yl)-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 15hexaen- 14-yl]cyclopropane- 1 -carboxamide(lS,2R)-2-[5-(difluoromethyl)pyrimidin-2-yl]-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 16hexaen- 14-yl]cyclopropane- 1 -carboxamide1 - { [5 -(fluoromethyl)pyridin-2-yl]methyl } - 3- { 3-methyl-7, 10-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 1714-yl} urea(lS,2R)-N-[(8R*)-8-hydroxy-3,8-dimethyl-10-oxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 1814-yl] -2- (5 -methylpyridin-2-yl)cyclopropane- 1 -carboxamide (stereoisomer 1 ) ( 1 S,2R)-N-[(8R*)-8-hydroxy-3,8-dimethyl- 10-oxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 1914-yl]-2-(5-methylpyridin-2-yl)cyclopropane-l -carboxamide (stereoisomer 2) (1 S,2R)-N-[(8R)-3,8-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 2014-yl]-2- [5 -(fluoromethyl)pyridin-2-yl]cyclopropane-l -carboxamiderel-(l R,2S)-2-(4-methyl- 1 H-pyrazol- 1 -yl)-N- { 3-methyl-7, 10-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 2114-yl} cyclopropane- 1 -carboxamide (stereoisomer 1)rel-(l R,2S)-2-(4-methyl- IH-pyrazol- 1 -yl)-N- { 3-methyl-7, 10-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 2214-yl} cyclopropane- 1 -carboxamide (stereoisomer 2)(lS,2R)-2-(5-cyclopropylpyrimidin-2-yl)-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 23hexaen-14-yl]cyclopropane-l -carboxamide(lS,2R)-N-{3-methyl-7,ll-dioxa-3,4,16,17- I- tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca-l(12),2(6),4,13,15,18-hexaen- 2415-yl}-2-[5-(trifluoromethyl)pyrimidin-2-yl]cyclopropane-l -carboxamiderel-3-{3-methyl-7,ll-dioxa-3,4,16,17- I- tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca-l(12),2(6),4,13,15,18-hexaen- 2515 -yl } - 1 - [( 1 R)- 1 -(5 -methylpyrimidin-2-yl)ethyl]urea (stereoisomer 1 )rel-3- { 3-methyl-7, 11 -dioxa-3,4, 16,17- I- tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca-l(12),2(6),4,13,15,18-hexaen- 2615 -yl } - 1 - [( 1 R)- 1 -(5 -methylpyrimidin-2-yl)ethyl]urea (stereoisomer 2)(lS,2R)-N-[3-(difluoromethyl)-7,l l-dioxa-3,4,16,17- I- tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca-l(12),2(6),4,13,15,18-hexaen- 2715-yl]-2-(5-methylpyrimidin-2-yl)cyclopropane-l-carboxamide(lS,2R)-N-[(8R*)-8-(hydroxymethyl)-3,8-dimethyl-9-oxa-3,4,14,15- I- tetraazatetracyclo[8.7.0.0A{2,6}.0A{ll,15}]heptadeca-l(10),2(6),4,ll,13,16-hexaen- 2813-yl]-2-(5-methylpyridin-2-yl)cyclopropane-l-carboxamide (stereoisomer 1) (lS,2R)-N-[(8R*)-8-(hydroxymethyl)-3,8-dimethyl-9-oxa-3,4,14,15- I- tetraazatetracyclo[8.7.0.0A{2,6}.0A{ll,15}]heptadeca-l(10),2(6),4,ll,13,16-hexaen- 2913-yl]-2-(5-methylpyridin-2-yl)cyclopropane-l -carboxamide (stereoisomer 2) ( 1 S,2R)-N - { 3-methyl- 10-oxa-4,5,6, 15,16- I- pentaazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2,4,12,14,17-hexaen-14- 30yl }-2-(5-methylpyridin-2-yl)cyclopropane- 1 -carboxamide( 1 S,2R)-2- [5 -(difluoro methyl)pyrimidin-2-yl]-N- [( 10R)-3, 10-dimethyl-7, 11 -dioxa- I- 3,4,16,17-tetraazatetracyclo[10.7.0.0A{2,6}.0A{ 13,17}]nonadeca- 311 (12), 2(6), 4, 13,15,18-hexaen- 15 -yl]cyclopropane- 1 -carboxamide(lS,2R)-2-(5-methylpyrimidin-2-yl)-N-[(8R,10R)-3,8,10-trimethyl-7,ll-dioxa- I- 3,4,16,17-tetraazatetracyclo[10.7.0.0A{2,6}.0A{ 13,17}]nonadeca- 321 ( 12), 2(6),4, 13, 15, 18-hexaen- 15 -yl]cyclopropane- 1 -carboxamide(lS,2R)-2-[5-(difluoromethyl)pyrimidin-2-yl]-N-[(8R,10R)-3,8,10-trimethyl-7,ll- I- dioxa-3,4,16,17-tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca- 331 ( 12), 2(6), 4, 13,15,18-hexaen- 15-yl]cyclopropane- 1 -carboxamide3-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 3414-yl]- 1 - [(5 -methylpyrimidin-2-yl)methyl]ureaN- { 3-methyl-7, 11 -dioxa-3,4, 16,17- I- tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca-l(12),2(6),4,13,15,18-hexaen- 3515 -yl } -3-(5-methylpyridin-2-yl)propanamide( 1 S,2R)-N- { 3-methyl-7, 10-dioxa-3,4, 12,15- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,13,15,17-hexaen- 3614-yl }-2-(5-methylpyridin-2-yl)cyclopropane-l -carboxamide(lS,2R)-N-{3,10-dimethyl-7-oxa-3,4,10,16,17- I- pentaazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca-l(12),2(6),4,13,15,18-hexaen- 3715-yl }-2-(5-methylpyridin-2-yl)cyclopropane-l -carboxamide(lS,2R)-2-[5-(difluoromethyl)pyrimidin-2-yl]-N-[(9R*)-3,9-dimethyl-10-oxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 38hexaen-14-yl]cyclopropane-l -carboxamide (stereoisomer 1)(lS,2R)-2-[5-(difluoromethyl)pyrimidin-2-yl]-N-[(9R*)-3,9-dimethyl-10-oxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 39hexaen-14-yl]cyclopropane-l -carboxamide (stereoisomer 2)(lS,2R)-2-[5-(difluoromethyl)pyrimidin-2-yl]-N-[(8R)-3,8-dimethyl-7,ll-dioxa- I- 3,4,16,17-tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca- 401 ( 12), 2(6), 4, 13,15,18-hexaen- 15 -yl] cyclopropane- 1 -carboxamide3-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 4114-yl]-l-[(lR*)-l-(5-methylpyrimidin-2-yl)ethyl]urea (stereoisomer 1)3-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 4214-yl]-l-[(lR*)-l-(5-methylpyrimidin-2-yl)ethyl]urea (stereoisomer 2)rel-3- { 3-methyl-7, 10-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 4314-yl } - 1 -[( 1 R)- 1 -(5-methylpyrimidin-2-yl)ethyl]urea (stereoisomer 1 )rel-3- { 3-methyl-7, 10-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 4414-yl } - 1 - [( 1 R)- 1 -(5 -methylpyrimidin-2-yl)ethyl]urea (stereoisomer 2)N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 4514-yl]-3-(5-methylpyrimidin-2-yl)propanamide(lS,2R)-N-{3,8-dimethyl-3,4,8,15,16- I- pentaazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 4614-yl } -2-(5 -methylpyridin-2-yl)cyclopropane- 1 -carboxamide( 1 S,2R)-N- { 3-methyl-9-oxo-7, 11 -dioxa-3,4, 16,17- I- tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca-l(12),2(6),4,13,15,18-hexaen- 4715 -yl } -2-(5-methylpyridin-2-yl)cyclopropane- 1 -carboxamide(1 S,2R)-N-{4-methyl-l l-oxa-5,16,17- I- triazatetracyclo[10.7.0.0A{2,7}.0A{13,17}]nonadeca-l(12),2(7),3,5,13,15,18-heptaen- 4815-yl } -2-(5-methylpyrimidin-2-yl)cyclopropane- 1 -carboxamide(lS,2R)-2-[5-(difluoromethyl)pyridin-2-yl]-N-[(9R*)-9-hydroxy-3,9-dimethyl-7,ll- I- dioxa-3,4,16,17-tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca- 491 (12), 2(6), 4, 13,15,18-hexaen- 15-yl]cyclopropane- 1 -carboxamide (stereoisomer 1 ) (lS,2R)-2-[5-(difluoromethyl)pyridin-2-yl]-N-[(9R*)-9-hydroxy-3,9-dimethyl-7,ll- I- dioxa-3,4,16,17-tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca- 501 (12), 2(6), 4, 13, 15, 18-hexaen- 15-yl]cyclopropane- 1 -carboxamide (stereoisomer 2) ( 1 S,2R)-2-(5-chloropyrimidin-2-yl)-N- { 3-methyl-7, 11 -dioxa-3,4, 16,17- I- tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca-l(12),2(6),4,13,15,18-hexaen- 5115-yl (cyclopropane- 1 -carboxamide( 1 S,2R)-N- { 3-methyl-5, 10-dioxa-4, 15,16- I- triazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),3,12,14,17-hexaen-14- 52yl } -2-(5 -methylpyrimidin-2-yl)cyclopropane- 1 -carboxamide(1 S,2R)-2- [5-(difluoromethyl)pyrimidin-2-yl]-N- { 3-methyl- 10-oxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 5314-yl } cyclopropane- 1 -carboxamide( 1 S,2R)-N-[(9R)-3,9-dimethyl-7, 10-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 5414-yl]-2- [5 -(3-fluoroazetidin-l-yl)pyridin-2-yl]cyclopropane-l -carboxamide (lS,2R)-2-[5-(3,3-difluoroazetidin-l-yl)pyridin-2-yl]-N-[(9R)-3,9-dimethyl-7,10- I- dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca- 551(11), 2(6), 4, 12, 14, 17 -hexaen- 14-yl] cyclopropane- 1 -carboxamide(lS,2R)-2-(5-{bicyclo[l.l.l]pentan-l-yl}pyrimidin-2-yl)-N-[(9R)-3,9-dimethyl-7,10- I- dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 561(11 ),2(6),4, 12,14,17 -hexaen- 14-yl] cyclopropane- 1 -carboxamide( 1 S,2R)-N- { 3-methyl-7, 12-dioxa-3,4, 17,18- I- tetraazatetracyclo[11.7.0.0A{2,6}.0A{14,18}]icosa-l(13),2(6),4,14,16,19-hexaen-16- 57yl } -2-(5 -methylpyrimidin-2-yl)cyclopropane- 1 -carboxamide(lS,2R)-N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 5814-yl] -2- { 5- [(2R)-2-methylazetidin- 1 -yl]pyrimidin-2-yl } cyclopropane- 1 -carboxamide (lS,2R)-2-[5-(l,l-difluoroethyl)pyrimidin-2-yl]-N-[(9R)-3,9-dimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17- 59hexaen- 14-yl] cyclopropane- 1 -carboxamide(lS,2R)-N-[(9R*)-9-(difluoromethyl)-3-methyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 6014-yl]-2-(5 -methylpyrimidin-2-yl)cyclopropane- 1 -carboxamide (stereoisomer 1 ) (lS,2R)-N-[(9R*)-9-(difluoromethyl)-3-methyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 6114-yl]-2-(5-methylpyrimidin-2-yl)cyclopropane-l -carboxamide (stereoisomer 2) (3R*)-N-[(9R)-3,9-dimethyl-7,l0-dioxa-3,4,15,l6- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 6214-yl]-4,4-difluoro-3-(4-methyl- 1 H-pyrazol- 1 -yl)butanamide (stereoisomer 1 ) (IS,2R)-N-[(9R)-3,9-dimethyl-7,l 0-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 6314-yl] -2- [5 -(3-methylazetidin- 1 -yl)pyridin-2-yl]cyclopropane- 1 -carboxamide (3R*)-N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 6414-yl]-4,4-difluoro-3-(4-methyl-l H-pyrazol- l-yl)butanamide (stereoisomer 2) (lS,2R)-2-[5-(azetidin-l-yl)pyrimidin-2-yl]-N-[(9R)-3,9-dimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 65hexaen-14-yl]cyclopropane-l -carboxamide(lS,2R)-N-{3-methyl-7,ll-dioxa-3,4,16,17- I- tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca-l(12),2(6),4,13,15,18-hexaen- 66 15 -yl } -2-(5 - { 2-oxabicyclo [2.1.1 ]hexan-4-yl } pyrimidin-2-yl)cyclopropane- 1 - carboxamide(lS,2R)-N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 67 14-yl]-2-(5 - { 2-oxabicyclo[2.1.1 ]hexan-4-yl }pyrimidin-2-yl)cyclopropane- 1 - carboxamide( 1 S,2R)-2-(5-cyanopyrimidin-2-yl)-N-[(9R)-3,9-dimethyl-7, 10-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 6814-yl]cyclopropane- 1 -carboxamide(3R*)-N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 6914-yl]-3-(5-methylpyridin-2-yl)butanamide (stereoisomer 1)(3R*)-N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 7014-yl]-3-(5-methylpyridin-2-yl)butanamide (stereoisomer 2)(lS,2R)-2-[5-(3,3-difluoroazetidin-l-yl)pyrimidin-2-yl]-N-[(9R)-3,9-dimethyl-7,10- I- dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca- 711(11), 2(6), 4, 12, 14, 17 -hexaen- 14-yl] cyclopropane- 1 -carboxamide(lS,2R)-2-(5-methylpyrimidin-2-yl)-N-[(8RS,9SR)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17- 72hexaen- 14-yl] cyclopropane- 1 -carboxamide(IS,2R)-N-[(9R)-3,9-dimethyl-7, 10-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 7314-yl] -2- [5 -(3-fluoroazetidin- 1 -yl)pyrimidin-2-yl]cyclopropane- 1 -carboxamide (lS,2R)-N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 7414-yl]-2- [5 -(3-methylazetidin- 1 -yl)pyrimidin-2-yl]cyclopropane- 1 -carboxamide (1 S,2R)-N-[(9R*)-9-(dimethylamino)-3-methyl-7,l l-dioxa-3,4,16,17- I- tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca-l(12),2(6),4,13,15,18-hexaen- 7515 -yl]-2-(5 -methylpyridin-2-yl)cyclopropane- 1 -carboxamide (stereoisomer 1 ) (lS,2R)-N-[(9R*)-9-(dimethylamino)-3-methyl-7,ll-dioxa-3,4,16,17- I- tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca-l(12),2(6),4,13,15,18-hexaen- 7615-yl]-2-(5-methylpyridin-2-yl)cyclopropane-l-carboxamide (stereoisomer 2) (IS,2R)-N-[(9R)-3,9-dimethyl-7, 10-dioxa-3,4, 15, 16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 7714-yl]-2- [5 -( 1 -hydro xycyclopropyl)pyrimidin-2-yl]cyclopropane- 1 -carboxamide (lS,2R)-N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 78 14-yl]-2-{5-[l-(dimethylamino)cyclopropyl]pyridin-2-yl}cyclopropane-l- carboxamideN-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 7914-yl]-2-( 1 -methyl- 1 H-pyrazol-3-yl)acetamide(lS,2R)-N-[(8R*)-3,8-dimethyl-9-oxa-3,4,14,15- I- tetraazatetracyclo[8.7.0.0A{2,6}.0A{ ll,15}]heptadeca-l(10),2(6),4,ll,13,16-hexaen- 8013-yl]-2-(5-methylpyrimidin-2-yl)cyclopropane-l -carboxamide (stereoisomer 2) (lS,2R)-2-(5-cyclopropylpyrimidin-2-yl)-N-[(8R*)-3,8-dimethyl-9-oxa-3,4,14,15- I- tetraazatetracyclo[8.7.0.0A{2,6}.0A{ll,15}]heptadeca-l(10),2(6),4,ll,13,16-hexaen- 8113-yl]cyclopropane-l -carboxamide (stereoisomer 1)( 1 S,2R)-2-(5 -cyclopropylpyrimidin-2-yl)-N- [(8R*)-3,8-dimethyl-9-oxa-3,4, 14,15- I- tetraazatetracyclo[8.7.0.0A{2,6}.0A{ll,15}]heptadeca-l(10),2(6),4,ll,13,16-hexaen- 8213-yl]cyclopropane-l -carboxamide (stereoisomer 2)(lS,2R)-N-[(8R*)-3,8-dimethyl-9-oxa-3,4,14,15- I- tetraazatetracyclo[8.7.0.0A{2,6}.0A{ll,15}]heptadeca-l(10),2(6),4,ll,13,16-hexaen- 8313-yl]-2-(5-methylpyrimidin-2-yl)cyclopropane-l -carboxamide (stereoisomer 1) (lS,2R)-2-[5-(difluoromethyl)pyrimidin-2-yl]-N-[(8R*)-3,8-dimethyl-9-oxa- I- 3, 4,14, 15-tetraazatetracyclo[8.7.0.0A{ 2,6}.0A{ 11,15 }]heptadeca- 841 ( 10),2(6),4, 11,13,16-hexaen- 13-yl]cyclopropane- 1 -carboxamide (stereoisomer 1 ) (lS,2R)-2-[5-(difluoromethyl)pyrimidin-2-yl]-N-[(8R*)-3,8-dimethyl-9-oxa- I- 3,4,14,15-tetraazatetracyclo[8.7.0.0A{2,6}.0A{ ll,15}]heptadeca- 851 (10), 2(6), 4, 11,13,16-hexaen- 13-yl]cyclopropane- 1 -carboxamide (stereoisomer 2) (lS,2R)-2-{5-[l-(difluoromethyl)cyclopropyl]pyrimidin-2-yl}-N-[(9R)-3,9-dimethyl- I- 7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 861 (11 ), 2(6), 4, 12, 14, 17 -hexaen- 14- yl] cyclopropane- 1 -carboxamide(lS,2R)-2-{5-[(lR*)-2,2-difluorocyclopropyl]pyrimidin-2-yl}-N-[(9R)-3,9-dimethyl- I- 7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 871(11 ),2(6),4, 12,14,17 -hexaen- 14-yl]cyclopropane- 1 -carboxamide (stereoisomer 1 ) (1 S,2R)-2-{5-[(lR*)-2,2-difluorocyclopropyl]pyrimidin-2-yl}-N-[(9R)-3,9-dimethyl- I- 7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 881 ( 11 ),2(6),4, 12,14,17 -hexaen- 14-yl]cyclopropane- 1 -carboxamide (stereoisomer 2) (IS,2R)-N-[(9R)-3,9-dimethyl-7,l 0-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 8914-yl]-2- [5 -( 1 -fluorocyclopropyl)pyrimidin-2-yl]cyclopropane- 1 -carboxamide (lS,2R)-2-[5-(2H3)methylpyrimidin-2-yl]-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 90hexaen- 14-yl]cy clopropane- 1 -carboxamide( 1 S,2R)-N-[(9R)-3,9-dimethyl- 10-oxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 9114-yl]-2-[5-(2H3)methylpyrimidin-2-yl]cyclopropane-l -carboxamide(lR*)-l-(5-methylpyrimidin-2-yl)ethyl N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 9214-yl]carbamate (stereoisomer 1)(lR*)-l-(5-methylpyrimidin-2-yl)ethyl N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 9314-yl]carbamate (stereoisomer 2)l-[(lR)-l-[5-(difluoromethyl)pyrimidin-2-yl]ethyl]-3-[(9R)-3,9-dimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 94hexaen-14-yl]urea(lS,2R)-N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 9514-yl]-2- [5 -(3-methyloxetan-3-yl)pyridin-2-yl]cyclopropane- 1 -carboxamide(lS,2R)-2-[5-(3,3-difluoroazetidin-l-yl)pyrimidin-2-yl]-N-[(8R,9R)-3,8,9-trimethyl- I- 7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16]]octadeca- 961(11 ),2(6),4, 12,14, 17-hexaen- 14-yl] cyclopropane- 1 -carboxamidel-[(lR)-l-[5-(difluoromethyl)pyridin-2-yl]ethyl]-3-{3-methyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 9714-yl} urea(lS,2R)-2-(5-{3-azabicyclo[3.1.0]hexan-3-yl]pyrimidin-2-yl)-N-[(9R)-3,9-dimethyl- I- 7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 981 ( 11 ),2(6),4, 12,14,17 -hexaen- 14-yl]cyclopropane- 1 -carboxamide(lS,2R)-2-[5-(3-fluoroazetidin-l-yl)pyrimidin-2-yl]-N-[(8R,9R)-3,8,9-trimethyl-7,10- I- dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca- 991(11 ),2(6),4, 12,14,17 -hexaen- 14-yl]cyclopropane- 1 -carboxamide3-[(9R)-3,9-dimethyl-7, 10-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 0014-yl]- 1 - [(8R)-5,6,7,8-tetrahydroquinolin-8-yl]urea3-[(9R)-3,9-dimethyl-7, 10-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 0114-yl]-l-[(8S)-5,6,7,8-tetrahydroquinolin-8-yl]ureal-{[5-(difluoromethyl)pyridin-2-yl]methyl}-3-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 02hexaen-14-yl]urea(IS,2R)-N-[(9R)-3,9-dimethyl-7,l 0-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 03 14-yl]-2-{5-[(2R*)-2-methyloxetan-2-yl]pyridin-2-yl}cyclopropane-l-carboxamide (stereoisomer 1)(lS,2R)-N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 04 14-yl]-2-{5-[(2R*)-2-methyloxetan-2-yl]pyridin-2-yl}cyclopropane-l-carboxamide (stereoisomer 2)(1 S,2R)-2-[5-(2-hydroxypropan-2-yl)pyridin-2-yl]-N-[(8R,9R)-3,8,9-trimethyl-7,10- I- dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca- 051 ( 11 ),2(6),4, 12,14,17 -hexaen- 14-yl]cyclopropane- 1 -carboxamide(lS,2R)-2-[5-(2-hydroxypropan-2-yl)pyrazin-2-yl]-N-[(8R,9R)-3,8,9-trimethyl-7,10- I- dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6].0A{12,16]]octadeca- 061(11), 2(6), 4, 12, 14, 17 -hexaen- 14-yl] cyclopropane- 1 -carboxamide(lS,2R)-2-[5-(3,3-difluoroazetidin-l-yl)pyrazin-2-yl]-N-[(9R)-3,9-dimethyl-7,10- I- dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 071 (11 ), 2(6), 4, 12, 14, 17 -hexaen- 14-yl]cyclopropane- 1 -carboxamide(lS,2R)-2-[5-(difluoromethyl)pyridin-2-yl]-N-[(9R)-3-methyl-7,16-dioxa- I- 3,4,13,21,22-pentaazapentacyclo[15.7.0.0A{2,6}.0A{9,13}.0A{18,22}]tetracosa- 08l(17),2(6),4,18,20,23-hexaen-20-yl]cyclopropane-l-carboxamide( 1 S,2R)-N-[(9R)-3,9-dimethyl-7, 10-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 09 14-yl] -2-(5 - { 2-oxabicyclo[2.1.1 ]hexan-4-yl }pyridin-2-yl)cyclopropane- 1 - carboxamide(lS,2R)-2-[5-(3,3-difluoroazetidin-l-yl)pyrazin-2-yl]-N-[(8R,9R)-3,8,9-trimethyl- I- 7, 10-dioxa-3,4, 15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 101(11 ),2(6 ),4, 12,14,17 -hexaen- 14-yl] cyclopropane- 1 -carboxamide3-[(9R)-3,9-dimethyl-7, 10-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 1114-yl]-l-[(lR*)-2,2,2-trifluoro-l-(5-methylpyrimidin-2-yl)ethyl]urea (stereoisomer 1) 3-[(9R)-3,9-dimethyl-7, 10-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 1214-yl]-l-[(lR*)-2,2,2-trifluoro-l-(5-methylpyrimidin-2-yl)ethyl]urea (stereoisomer 2) (lS,2R)-2-[5-(difluoromethyl)pyrimidin-2-yl]-N-{3-methyl-7,10-dioxa-13-thia- I- 3,4,15-triazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12(16),14,17- 13hexaen- 14-yl } cyclopropane- 1 -carboxamide(1 S,2R)-2-(5- { 2-oxabicyclo[2.1.1 ]hexan-4-yl}pyrimidin-2-yl)-N-[(8R,9R)-3,8,9- I- trimethyl-7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca- 141 (11 ), 2(6), 4, 12, 14, 17 -hexaen- 14-yl]cyclopropane- 1 -carboxamiderel-3-{3-methyl-7,10-dioxa-13-thia-3,4,15- I- triazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(18),2(6),4,ll,14,16-hexaen-14- 15yl } - 1 - [( 1 R)- 1 -(5 -methylpyrimidin-2-yl)ethyl]urea (stereoisomer 1 )rel-3-{3-methyl-7,10-dioxa-13-thia-3,4,15- I- triazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(18),2(6),4,ll,14,16-hexaen-14- 16yl }- 1 -[(1 R)-l -(5-methylpyrimidin-2-yl)ethyl]urea (stereoisomer 2)(lS,2R)-N-[(14S)-3-methyl-7,16-dioxa-3,4,10,21,22- I- pentaazapentacyclo[15.7.0.0A{2,6}.0A{10,14}.0A{ 18,22}]tetracosa- 17 1(17), 2(6), 4, 18,20, 23-hexaen-20-yl]-2-(5-methylpyrimidin-2-yl)cyclopropane-l- carboxamide(1 S,2R)-2-[5-(difluoromethyl)pyridin-2-yl]-N-[(14S)-3-methyl-7,16-dioxa- I- 3,4,10,21,22-pentaazapentacyclo[15.7.0.0A{2,6}.0A{ 10,14}.0A{18,22}]tetracosa- 18l(17),2(6),4,18,20,23-hexaen-20-yl]cyclopropane-l-carboxamide(IS,2R)-N-[(9R)-3,9-dimethyl-7,l 0-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16]]octadeca-l(l l),2(6),4,12,14,17-hexaen- 19 14-yl]-2-(5 - { 3-fluorobicyclo[l.1.1 ]pentan- 1 -yl }pyrimidin-2-yl)cyclopropane- 1 - carboxamide(lS,2R)-2-[5-(difluoromethyl)pyrimidin-2-yl]-N-[(8R,12R)-3-methyl-7,14-dioxa- I- 3,4,ll,19,20-pentaazapentacyclo[13.7.0.0A{2,6}.0A{8,12}.0A{ 16,20}]docosa- 201 (15), 2(6), 4, 16,18,21 -hexaen- 18-yl]cyclopropane- 1 -carboxamide(1 S,2R)-2- [5-(difluoromethyl)pyridin-2-yl]-N- [( 14S)-3-methyl-9-oxo-7, 16-dioxa- I- 3,4,10,21,22-pentaazapentacyclo[15.7.0.0A{2,6}.0A{10,14}.0A{18,22}]tetracosa- 21l(17),2(6),4,18,20,23-hexaen-20-yl]cyclopropane-l-carboxamidel-[(lR)-l-[5-(difluoromethyl)pyrimidin-2-yl]ethyl]-3-[(8R,9R)-3,8,9-trimethyl-7,10- I- dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 221(11 ),2(6),4, 12,14, 17-hexaen- 14-yl]urea(lS,2R)-2-[5-(difluoromethyl)pyrimidin-2-yl]-N-[(8RS, HSR)-3-methyl-7,12-dioxa- I- 3,4,17,18-tetraazapentacyclo[11.7.0.0A{2,6}.0A{8,ll}.0A{ 14,18}]icosa- 231 ( 13), 2(6), 4, 14,16, 19-hexaen- 16-yl]cyclopropane- 1 -carboxamide3- { 9,9-difluoro-3-methyl-7, 11 -dioxa-3,4, 16,17- I- tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca-l(12),2(6),4,13,15,18-hexaen- 2415 -yl } - 1 - [( 1 R)- 1 - [5 -(difluoromethyl)pyrimidin-2-yl]ethyl]urea(lS,2R)-2-(5-{ l-methyl-2-oxabicyclo[2.1.1]hexan-4-yl}pyrimidin-2-yl)-N-[(8R,9R)- I- 3,8,9-trimethyl-7, 10-dioxa-3,4, 15,16- 25 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl]cyclopropane- 1 -carboxamide(lS,2R)-2-(5-methylpyrimidin-2-yl)-N-[(8R*,9R*)-3,8,9-trimethyl-7,10-dioxa- I- 3, 4,12, 15-tetraazatetracyclo[9.7.0.0A{ 2,6}.0A{ 12, 16}]octadeca-l (11), 2(6), 4, 13, 15, 17- 26hexaen- 14-yl]cyclopropane-l -carboxamide (stereoisomer 1)(lS,2R)-2-(5-methylpyrimidin-2-yl)-N-[(8R*,9R*)-3,8,9-trimethyl-7,10-dioxa- I- 3, 4, 12, 15-tetraazatetracyclo[9.7.0.0A{ 2,6}.0A{ 12, 16}]octadeca-l (11), 2(6), 4, 13, 15, 17- 27hexaen- 14-yl]cyclopropane-l -carboxamide (stereoisomer 2)( 1 S,2R)-2- [5-(difluoromethyl)pyridin-2-yl]-N- [(8R, 12R)-3-methyl-7, 14-dioxa- I- 3,4,ll,19,20-pentaazapentacyclo[13.7.0.0A{2,6}.0A{8,12}.0A{16,20}]docosa- 281 (15), 2(6), 4, 16, 18,21 -hexaen- 18-yl]cyclopropane- 1 -carboxamide(lS,2R)-2-[5-(difluoromethyl)pyridin-2-yl]-N-[(8R,12R)-3,ll-dimethyl-7,14-dioxa- I- 3,4,ll,19,20-pentaazapentacyclo[13.7.0.0A{2,6}.0A{8,12}.0A{16,20}]docosa- 291 (15), 2(6), 4,16,18,21 -hexaen- 18-yl]cyclopropane-l -carboxamide2-( 1 -methyl- 1 H-pyrazol-3-yl)-N-[(8R,9R)-3,8,9-trimethyl-7, 10-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 3014-yl] acetamide(IS,2R)-2- [5-(difluoromethyl)pyridin-2-yl]-N- [(9R)-3-methyl- 14-oxo-7, 16-dioxa- I- 3,4,13,21,22-pentaazapentacyclo[15.7.0.0A{2,6}.0A{9,13}.0A{l 8,22}]tetracosa- 31l(17),2(6),4,18,20,23-hexaen-20-yl]cyclopropane-l-carboxamide( 1 S,2R)-2- [5-(difluoromethyl)pyridin-2-yl]-N- [3-( 1 -hydroxy ethyl) -5, 10-dioxa- I- 4,15,16-triazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),3,12,14,17- 32hexaen- 14-yl]cyclopropane- 1 -carboxamide(lS,2R)-N-[(9R)-3-methyl-7,16-dioxa-3,4,13,21,22- I- pentaazapentacyclo[15.7.0.0A{2,6}.0A{9,13}.0A{ 18,22}]tetracosa- 33 1 ( 17), 2(6), 4, 18,20,23-hexaen-20-yl]-2-(5 -methylpyrimidin-2-yl)cyclopropane- 1 - carboxamide2-(l-methyl-lH-pyrazol-3-yl)-N-[(8R,12R)-3-methyl-7,14-dioxa-3, 4, 11,19,20- I- pentaazapentacyclo[13.7.0.0A{2,6}.0A{8,12}.0A{ 16,20}]docosa- 341 ( 15), 2(6), 4, 16,18,21 -hexaen- 18-yl] acetamide(3R*)-3-(5 -methylpyrimidin-2-yl)-N- [(8R,9R)-3,8,9-trimethyl-7, 10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 3514-yl]butanamide (stereoisomer 1)l-{[(2S)-oxolan-2-yl]methyl}-3-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 3614-yl]urea(lS,2R)-2-[5-(difluoromethyl)pyridin-2-yl]-N-[8-(hydroxymethyl)-3,8-dimethyl-9- I- oxa-3,4,14,15-tetraazatetracyclo[8.7.0.0A{2,6}.0A{11,15}]heptadeca- 371 ( 10),2(6),4, 11,13,16-hexaen- 13-yl]cyclopropane- 1 -carboxamide(3R*)-3-(5-methylpyrimidin-2-yl)-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 3814-yl]butanamide (stereoisomer 2)2-(2-methyl-l,3-thiazol-4-yl)-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 3914-yl]acetamide3-( 1 -methyl- 1 H-pyrazol-3-yl)-N-[(8R,9R)-3,8,9-trimethyl-7, 10-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 4014-yl]propanamideN-[(8R,12R)-3,1 l-dimethyl-7,14-dioxa-3, 4,11,19,20- I- pentaazapentacyclo[13.7.0.0A{2,6}.0A{8,12}.0A{16,20}]docosa- 411 ( 15), 2(6), 4, 16,18,21 -hexaen- 18-yl] -2- ( 1 -methyl- 1 H-pyrazol-3-yl)acetamide3-[(lR,2S)-2-methoxycyclobutyl]-l-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 4214-yl]urea( 1 S,2R)-2- [5-(difluoromethyl)pyrimidin-2-yl]-N- [(8R, 12R)-3, 11 -dimethyl-7, 14- I- dioxa-3,4,11,19,20-pentaazapentacyclo[13.7.0.0A{2,6}.0A{8,12}.0A{16,20}]docosa- 431 (15), 2(6), 4, 16, 18,21 -hexaen- 18-yl]cyclopropane- 1 -carboxamide3-[4-(3,3,3-trifluoropropanoyl)piperazin-l-yl]-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 44hexaen-14-yl]propanamide(3R*)-4,4-difluoro-3-(5-methylpyrimidin-2-yl)-N-[(8R,9R)-3,8,9-trimethyl-7,10- I- dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca- 451(11), 2(6), 4, 12, 14, 17 -hexaen- 14-yl]butanamide (stereoisomer 1 )(3R*)-4,4-difluoro-3-(5-methylpyrimidin-2-yl)-N-[(8R,9R)-3,8,9-trimethyl-7,10- I- dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 46l(ll),2(6),4,12,14,17-hexaen-14-yl]butanamide (stereoisomer 2)2-{5H,6H,7H-pyrazolo[3,2-b][l,3]oxazin-2-yl}-N-[(8R,9R)-3,8,9-trimethyl-7,10- I- dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 471(11), 2(6), 4, 12, 14, 17 -hexaen- 14-yl] acetamide(lS,2R)-2-(5-{2-oxabicyclo[2.1.1]hexan-l-yl}pyrimidin-2-yl)-N-[(8R,9R)-3,8,9- I- trimethyl-7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 481 ( 11 ),2(6),4, 12,14,17 -hexaen- 14-yl]cyclopropane- 1 -carboxamide2-{pyrazolo[l,5-a]pyridin-2-yl}-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16]]octadeca-l(l l),2(6),4,12,14,17-hexaen- 4914-yl] acetamide(lS,2R)-2-[5-(difluoromethyl)pyridin-2-yl]-N-[(2R*)-3'-methyl-7', H'-dioxa- I- 3', 4', 16', 17'-tetraazaspiro[oxetane-2,9'- 50 tetracyclo[10.7.0.0A{2,6}.0A{ 13,17}]nonadecane]-l'(12'),2'(6'),4',13',15',18'-hexaen- 15'-yl]cyclopropane-l-carboxamide (stereoisomer 1)1 -[( 1 R)- 1 - [5-(difluoromethyl)pyrimidin-2-yl]ethyl]-3- { 3-methyl-7, 11 -dioxa- I- 3,4,16,17-tetraazatetracyclo[10.7.0.0A{2,6}.0A{ 13,17}]nonadeca- 511 ( 12), 2(6),4, 13, 15, 18-hexaen- 15 -y 1 } urea(lS,2R)-2-[5-(difluoromethyl)pyridin-2-yl]-N-[(2R*)-3'-methyl-7', H'-dioxa- I- 3',4',16',17'-tetraazaspiro[oxetane-2,9'- 52 tetracyclo[10.7.0.0A{2,6}.0A{ 13,17}]nonadecane]-r(12'),2'(6'),4',13',15',18'-hexaen- 15'-yl]cyclopropane-l -carboxamide (stereoisomer 2)1 -[( 1 R)- 1 - [5-(difluoromethyl)pyrimidin-2-yl]ethyl]-3- { 3-methyl-7, 10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6].0A{12,16]]octadeca-l(ll),2(6),4,12,14,17- 53hexaen-14-yl}urea2-[(8R*)-5,6,7,8-tetrahydroquinolin-8-yl]-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 54hexaen-14-yl]acetamide (stereoisomer 1)2-[(8R*)-5,6,7,8-tetrahydroquinolin-8-yl]-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12, 16}]octadeca-l(ll), 2(6), 4,12, 14,17- 55hexaen-14-yl]acetamide (stereoisomer 2)3-[(2R*)-oxolan-2-yl]-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l (11 ), 2(6), 4,12,14,17-hexaen- 5614-yl]propanamide (stereoisomer 1)3-[(2R*)-oxolan-2-yl]-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 5714-yl]propanamide (stereoisomer 2)(1 S,2R)-N-[(8R*)-8-(2-hydroxypropan-2-yl)-3-methyl-9-oxa-3,4,14,15- I- tetraazatetracyclo[8.7.0.0A{2,6}.0A{ ll,15}]heptadeca-l(10),2(6),4,ll,13,16-hexaen- 5813 -yl] -2- (5 -methylpyridin-2-yl)cyclopropane-l -carboxamide (stereoisomer 1 ) (lS,2R)-N-[(8R*)-8-(2-hydroxypropan-2-yl)-3-methyl-9-oxa-3,4,14,15- I- tetraazatetracyclo[8.7.0.0A{2,6}.0A{ll,15}]heptadeca-l(10),2(6),4,ll,13,16-hexaen- 5913-yl]-2-(5-methylpyridin-2-yl)cyclopropane-l -carboxamide (stereoisomer 2) ( 1 S,2R)-N- { 3-methyl-7, 10-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 6014-yl } -2-[5-(propan-2-yloxy)pyridin-2-yl]cyclopropane- 1 -carboxamide(lS,2R)-2-[5-(propan-2-yloxy)pyrimidin-2-yl]-N-[(8R,9R)-3,8,9-trimethyl-7,10- I- dioxa-3,4, 15,16-tetraazatetracyclo [9.7,0.0A{ 2,6 }.0A{ 12, 16 } ]octadeca- 611(11), 2(6), 4, 12, 14, 17 -hexaen- 14-yl] cyclopropane- 1 -carboxamide(3R*)-4,4-difluoro-3-(4-methyl-lH-pyrazol-l-yl)-N-[(8R,9R)-3,8,9-trimethyl-7,10- I- dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 621(11), 2(6), 4,12, 14, 17-hexaen-14-yl]butanamide (stereoisomer 1)(3R*)-4,4-difluoro-3-(4-methyl-lH-pyrazol-l-yl)-N-[(8R,9R)-3,8,9-trimethyl-7,10- I- dioxa-3,4, 15,16-tetraazatetracyclo [9.7.0.0A{ 2,6 }.0A{ 12, 16 } ]octadeca- 631(1 l),2(6),4,12,14,17-hexaen-14-yl]butanamide (stereoisomer 2)2-(l,5-dimethyl-lH-pyrazol-3-yl)-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 6414-yl]acetamide3-{[(6R*)-5-oxa-2-azaspiro[3.4]octan-6-yl]methyl}-l-[(8R,9R)-3,8,9-trimethyl-7,10- I- dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca- 65l(ll),2(6),4,12,14,17-hexaen-14-yl]urea (stereoisomer 1)3-{[(6R*)-5-oxa-2-azaspiro[3.4]octan-6-yl]methyl}-l-[(8R,9R)-3,8,9-trimethyl-7,10- I- dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 66l(ll),2(6),4,12,14,17-hexaen-14-yl]urea (stereoisomer 2)(lR*)-l-(5-methylpyrimidin-2-yl)ethyl N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 67hexaen-14-yl]carbamate (stereoisomer 1)(1 R*)-l -(5-methylpyrimidin-2-yl)ethyl N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 68hexaen-14-yl]carbamate (stereoisomer 2)(lS,2R)-2-[5-(difluoromethyl)pyridin-2-yl]-N-[(8R*)-8-(hydroxymethyl)-3,8- I- dimethyl-9-oxa-3,4,14,15-tetraazatetracyclo[8.7.0.0A{2,6}.0A{ ll,15}]heptadeca- 691 ( 10),2(6),4, 11,13,16-hexaen- 13 -yl] cyclopropane- 1 -carboxamide (stereoisomer 1 ) (lS,2R)-2-[5-(difluoromethyl)pyridin-2-yl]-N-[(8R*)-8-(hydroxymethyl)-3,8- I- dimethyl-9-oxa-3,4,14,15-tetraazatetracyclo[8.7.0.0A{2,6}.0A{l l,15}]heptadeca- 701 ( 10),2(6),4, 11,13,16-hexaen- 13-yl]cyclopropane- 1 -carboxamide (stereoisomer 2) (6aR*,7S *,7aS*)-N-[(8R,9R)-3,8,9-trimethyl-7, 10-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 7114-yl]-5H,6H,6aH,7H,7aH-cyclopropa[h]quinoline-7-carboxamide (stereoisomer 1 ) (6aR*,7S*,7aS*)-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 7214-yl]-5H,6H,6aH,7H,7aH-cyclopropa[h]quinoline-7-carboxamide (stereoisomer 2) 2- { 1 - [2-(dimethylamino)ethyl]- 1 H-pyrazol-3-yl } -N- [(8R,9R)-3,8,9-trimethyl-7, 10- I- dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 73l(ll),2(6),4,12,14,17-hexaen-14-yl]acetamide (stereoisomer 1)2- { 1 - [2-(dimethylamino)ethyl]- 1 H-pyrazol-5 -yl } -N- [(8R,9R)-3,8,9-trimethyl-7, 10- I- dioxa-3,4, 15,16-tetraazatetracyclo [9.7,0.0A{ 2,6 }.0A{ 12, 16 } ]octadeca- 741(11), 2(6), 4, 12, 14, 17 -hexaen- 14-yl] acetamide (stereoisomer 2)2-( 1 - { bicyclo [1.1.1 ]pentan- 1 -yl } - 1 H-pyrazol-3-yl)-N- [(9R)-3,9-dimethyl-7, 10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 75hexaen- 14-yl] acetamide1 - [5-(difluoromethyl)pyrimidin-2-yl]ethyl N- [(9R)-3,9-dimethyl-7, 10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 76hexaen- 14-yl]carbamate(2R*)-N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 7714-yl]-2-(l -methyl- lH-pyrazol-3-yl)propanamide (stereoisomer 1)(2R*)-N-[(9R)-3,9-dimethyl-7, 10-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 7814-yl]-2-(l -methyl- lH-pyrazol-3-yl)propanami de (stereoisomer 2)3-(4-methyl- 1 H-pyrazol- 1 -yl)-N-[(8R,9R)-3,8,9-trimethyl-7, 10-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 7914-yl]propanamide2-( 1 -cyclopropyl- 1 H-pyrazol-3-yl)-N- [(9R)-3,9-dimethyl-7, 10-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 8014-yl] acetamideN-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 8114-yl]-2-(5-methylpyrimidin-2-yl)acetamideN-[(9R)-3,9-dimethyl-7,l 0-dioxa-3,4,l 5,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 8214-yl]-2-(5-methylpyridin-2-yl)acetamide3-[(lR*)-l-[(2R**)-oxolan-2-yl]ethyl]-l-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 83hexaen-14-yl]urea (stereoisomer 1)3-[(lR*)-l-[(2R**)-oxolan-2-yl]ethyl]-l-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 84hexaen-14-yl]urea (stereoisomer 2)3-[(lR*)-l-[(2R**)-oxolan-2-yl]ethyl]-l-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 85hexaen-14-yl]urea (stereoisomer 4)3-{[(6R*)-5-oxaspiro[3.4]octan-6-yl]methyl}-l-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 86hexaen-14-yl]urea (stereoisomer 1)3-{[(6R*)-5-oxaspiro[3.4]octan-6-yl]methyl}-l-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4, 15, 16-tetraazatetracyclo[9.7.0.0A{ 2, 6 }.0A{ 12, 16 } ]octadeca- 1 (11), 2(6), 4, 12, 14,17- 87hexaen-14-yl]urea (stereoisomer 2)3- { 3-methyl-7, 10-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 8814-yl } - 1 - [( 1 R)- 1 - [5 -(propan-2-yloxy)pyrimidin-2-yl]ethyl]urea(lS,2R)-2-[5-(difluoromethyl)-3-fluoropyridin-2-yl]-N-[(9R)-3,9-dimethyl-7,10- I- dioxa-3,4, 15,16-tetraazatetracyclo[9.7.0.0A{ 2,6 },0A{ 12, 16 }]octadeca- 891(11 ),2(6),4, 12,14, 17-hexaen- 14-yl]cyclopropane- 1 -carboxamiderel-l-[(R)-cyclopropyl[5-(difluoromethyl)pyrimidin-2-yl]methyl]-3-{3-methyl-7,10- I- dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 90l(ll),2(6),4,12,14,17-hexaen-14-yl}urea (stereoisomer 1)rel-l-[(R)-cyclopropyl[5-(difluoromethyl)pyrimidin-2-yl]methyl]-3-{3-methyl-7,10- I- dioxa-3,4, 15,16-tetraazatetracyclo[9.7.0.0A{ 2,6 },0A{ 12, 16 } ]octadeca- 91l(ll),2(6),4,12,14,17-hexaen-14-yl}urea (stereoisomer 2)l-{[(2R*)-l,8-dioxaspiro[4.5]decan-2-yl]methyl}-3-[(8R,9R)-3,8,9-trimethyl-7,10- I- dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca- 92l(ll),2(6),4,12,14,17-hexaen-14-yl]urea (stereoisomer 1)N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 9314-yl]-2-(2-methyl-l,3-oxazol-4-yl)acetamidel-{[(2R*)-l,8-dioxaspiro[4.5]decan-2-yl]methyl}-3-[(8R,9R)-3,8,9-trimethyl-7,10- I- dioxa- 3,4, 15,16-tetraazatetracyclo [9.7.0.0A{ 2,6 },0A{ 12, 16 }]octadeca- 94l(ll),2(6),4,12,14,17-hexaen-14-yl]urea (stereoisomer 2)( 1 R *)- 1 - [5 -(difluoromethyl)pyrimidin-2-yl]ethyl N- [(9R)-3,9 -dimethyl-7, 10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 95hexaen-14-yl]carbamate (stereoisomer 2)(lR*)-l-[5-(difluoromethyl)pyrimidin-2-yl]ethyl N-[(9R)-3,9-dimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 96hexaen-14-yl]carbamate (stereoisomer 1)N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 9714-yl] -2- (6 -methylpyridazin- 3 -yl) acetamideN-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 9814-yl]-2-(2-methyl- 1,3-thiazol-4-yl)acetamide3-[(lR*,4R**)-5-oxaspiro[3.4]octan-l-yl]-l-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 99hexaen-14-yl]urea (stereoisomer 1)3-[(lR*,4R**)-5-oxaspiro[3.4]octan-l-yl]-l-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 00hexaen-14-yl]urea (stereoisomer 2)3-[(lR*,4R**)-5-oxaspiro[3.4]octan-l-yl]-l-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4, 15, 16-tetraazatetracyclo[9.7.0.0A{ 2, 6 }.0A{ 12, 16 } ]octadeca- 1 (11), 2(6), 4, 12, 14,17- 01hexaen-14-yl]urea (stereoisomer 3)3-[(lR*,4R**)-5-oxaspiro[3.4]octan-l-yl]-l-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 02hexaen-14-yl]urea (stereoisomer 4)(3R*)-N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 03 14-yl]-4,4-difluoro-3-{2H,4H,6H,7H-pyrano[4,3-c]pyrazol-2-yl}butanamide (stereoisomer 2)(3R*)-N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 04 14-yl]-4,4-difluoro-3-{2H,4H,6H,7H-pyrano[4,3-c]pyrazol-2-yl}butanamide (stereoisomer 1)N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 0514-yl]-2-(4-methyl-l,3-thiazol-2-yl)acetamideN-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 0614-yl]-2-(5 -methyl- l,3-oxazol-2-yl)acetamidel-[(3-fluoro-5-methylpyridin-2-yl)methyl]-3-{3-methyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 0714-yl} ureal-[(5-{3-fluorobicyclo[l.l.l]pentan-l-yl}pyrimidin-2-yl)methyl]-3-{3-methyl-7,10- I- dioxa-3,4, 15,16-tetraazatetracy clo [9.7,0.0A{ 2,6 }.0A{ 12, 16 } ]octadeca- 081(11 ),2(6),4, 12,14,17 -hexaen- 14-yl }urea1 - { [5-(difluoromethyl)-3-fluoropyridin-2-yl]methyl } -3- { 3-methyl-7, 10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17- 09hexaen-14-yl}urea(9R)-3,9-dimethyl-N- {[(IS,2R)-2-(5 -methylpyridin-2-yl)cyclopropyl]methyl } -7, 10- I- dioxa-3, 4,15,16-tetraazatetracy clo[9.7.0.0A{ 2,6}.0A{ 12,16}]octadeca- 101(11), 2(6), 4, 12, 14, 17 -hexaen- 14-amineN-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 1114-yl]-2-(4-methyl-l,3-oxazol-2-yl)acetamide(1 S,2R)-2-[5-(difluoromethyl)pyridin-2-yl]-N-{3-[(lR*)-l-hydroxyethyl]-5,10-dioxa- I- 4,15,16-triazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),3,12,14,17- 12hexaen- 14-yl} cyclopropane- 1 -carboxamide (stereoisomer 1)(lS,2R)-2-[5-(difluoromethyl)pyridin-2-yl]-N-{3-[(lR*)-l-hydroxyethyl]-5,10-dioxa- I- 4,15,16-triazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),3,12,14,17- 13hexaen- 14-yl} cyclopropane- 1 -carboxamide (stereoisomer 2)(9R)-3,9-dimethyl-N-[2-(5-methylpyridin-2-yl)ethyl]-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 1414-amineN-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 1514-yl]acetamide2-{4H,6H,7H-pyrazolo[3,2-c][l,4]oxazin-2-yl}-N-[(8R,9R)-3,8,9-trimethyl-7,10- I- dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6].0A{12,16}]octadeca- 161(11), 2(6), 4,12, 14, 17 -hexaen- 14-yl] acetamide2-(5-methylpyrimidin-2-yl)-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 1714-yl] acetamide2-(5-methylpyridin-2-yl)-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 1814-yl]acetamide(4R *)-N-[(9R)-3,9-dimethyl-7, 10-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(l 1), 2(6), 4,12, 14,17-hexaen- 1914-yl]-2-methyl-4,5,6,7-tetrahydro-l,3-benzothiazole-4-carboxamide (stereoisomer 1) (4R*)-N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 2014-yl]-2-methyl-4,5,6,7-tetrahydro-l,3-benzothiazole-4-carboxamide (stereoisomer 2) 2-[l-(cyclopropylmethyl)-lH-pyrazol-3-yl]-N-[(9R)-3,9-dimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 21hexaen- 14-yl]acetamidel-[(lR*)-l-[(2R**)-oxolan-2-yl]ethyl]-3-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 22hexaen-14-yl]urea (stereoisomer 3)2-[l-(cyclopropylmethyl)-lH-pyrazol-5-yl]-N-[(9R)-3,9-dimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 23hexaen- 14-yl]acetamideN-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 2414-yl] -2- { 5H,6H,8H-imidazo[2, 1 -c] [ 1,4]oxazin-2-yl } acetamide(lS,2R)-2-[5-(difluoromethyl)pyrimidin-2-yl]-N-[(8R*,llS*)-3-methyl-7,12-dioxa- I- 3,4,17,18-tetraazapentacyclo[11.7.0.0A{2,6}.0A{8,ll}.0A{14,18}]icosa- 251 ( 13), 2(6), 4, 14,16,19-hexaen- 16-yl]cyclopropane- 1 -carboxamide (stereoisomer 1 ) (lS,2R)-2-[5-(difluoromethyl)pyrimidin-2-yl]-N-[(8R*, HS*)-3-methyl-7,12-dioxa- I- 3,4,17,18-tetraazapentacyclo[11.7.0.0A{2,6}.0A{8,ll}.0A{ 14,18}]icosa- 261 (13), 2(6), 4, 14,16, 19-hexaen- 16-yl]cyclopropane- 1 -carboxamide (stereoisomer 2) 2-[5-(difluoromethyl)pyridin-2-yl]-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 2714-yl] acetamiderel-l-[(R)-cyclopropyl(5-methylpyrimidin-2-yl)methyl]-3-{3-methyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 28hexaen-14-yl]urea (stereoisomer 1)rel-l-[(R)-cyclopropyl(5-methylpyrimidin-2-yl)methyl]-3-{3-methyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 29hexaen-14-yl}urea (stereoisomer 2)(1 S,2R)-2- [5-(difluoromethoxy)pyrimidin-2-yl]-N- [(9R)-3,9-dimethyl-7, 10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 30hexaen- 14-yl] cyclopropane- 1 -carboxamideN-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 3114-yl] -2- { 5- [( 1 -methyl- 1 H-pyrazol-4-yl)oxy]pyridin-2-yl Jacetamide3-{3-methyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 3214-yl}-l-{[5-(pentafluoro-lambda6-sulfanyl)pyridin-2-yl]methyl}urea(lS,2R)-2-(5-{3-fluorobicyclo[l.l.l]pentan-l-yl}pyrimidin-2-yl)-N-{3-methyl-7,10- I- dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6].0A{ 12,16}]octadeca- 331(11), 2(6), 4,12, 14, 17 -hexaen- 14-yl } cyclopropane- 1 -carboxamide(lS,2R)-N-[(8R*,llS*)-3-methyl-7,12-dioxa-3,4,17,18- I- tetraazapentacyclo[11.7.0.0A{2,6}.0A{8,ll}.0A{14,18}]icosa-l(13),2(6),4,14,16,19- 34 hexaen- 16-yl]-2-(5-methylpyrimidin-2-yl)cyclopropane- 1 -carboxamide (stereoisomer 1)(lS,2R)-N-[(8R*,llS*)-3-methyl-7,12-dioxa-3,4,17,18- I- tetraazapentacyclo[l 1.7.0.0A{ 2,6}.0A{ 8,11}.0A{ 14,18}]icosa-l(13), 2(6), 4, 14, 16,19- 35 hexaen-16-yl]-2-(5-methylpyrimidin-2-yl)cyclopropane-l-carboxamide (stereoisomer 2)(lS,2R)-2-[5-(difluoromethyl)pyridin-2-yl]-N-{3-methyl-7,10-dioxa-3,4,12,15- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,13,15,17-hexaen- 3614-yl } cyclopropane- 1 -carboxamide(lS,2R)-2-[5-(difluoromethyl)pyrimidin-2-yl]-N-[(9R)-3,9-dimethyl-7,10-dioxa- I- 3,4,12,15-tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l (11 ), 2(6), 4,13,15,17- 37hexaen- 14-yl]cy clopropane- 1 -carboxamide(lS,2R)-2-[5-(difluoromethyl)pyrimidin-2-yl]-N-[(8R*,9R*)-3,8,9-trimethyl-7,10- I- dioxa-3,4, 12,15 -tetraazatetracyclo [9.7,0.0A{ 2,6 }.0A{ 12, 16 } ]octadeca- 381(11 ),2(6),4, 13,15,17 -hexaen- 14- yl] cyclopropane- 1 -carboxamide (stereoisomer 1 ) (1 S,2R)-2-[5-(difluoromethyl)pyrimidin-2-yl]-N-[(8R*,9R*)-3,8,9-trimethyl-7,10- I- dioxa-3,4,12,15-tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca- 391 ( 11 ),2(6),4, 13,15,17 -hexaen- 14-yl]cyclopropane- 1 -carboxamide (stereoisomer 2) (lS,2R)-N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,12,15- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,13,15,17-hexaen- 4014-yl]-2-(5 -methylpyrimidin-2-yl)cyclopropane- 1 -carboxamiderel-3-[(lR)-l-(5-methyl-l,3-thiazol-2-yl)ethyl]-l-{3-methyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 4114-yl} urea (stereoisomer 2)N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 3214-yl]-2- { 5- [( 1 -methyl- 1 H-pyrazol-4-yl)methyl]pyridin-2-yl } acetamiderel-3-[(lR)-l-(5-methyl-l,3-thiazol-2-yl)ethyl]-l-{3-methyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16]]octadeca-l(l l),2(6),4,12,14,17-hexaen- 4314-yl}urea (stereoisomer 1)rel- 3 - [( 1 R)- 1 -( 1 -methyl- 1 H-pyrazol-3-yl)ethyl]- 1 - { 3-methyl-7, 10-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 4414-yl}urea (stereoisomer 1)rel-3- [( 1 R)- 1 -( 1 -methyl- 1 H-pyrazol-3-yl)ethyl]- 1 - { 3-methyl-7, 10-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 4514-yl}urea (stereoisomer 2)rel- 1 -[( 1 R)- 1 - [5-(difluoromethoxy)pyrimidin-2-yl]ethyl]-3- { 3-methyl-7, 10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17- 46hexaen-14-yl}urea( 1 S,2R)-N- { 3-methyl-7, 10-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 4714-yl}-2-[5-(pentafluoro-lambda6-sulfanyl)pyridin-2-yl]cyclopropane-l-carboxamide rel-l-[(lR)-2-methoxy-l-(5-methylpyrimidin-2-yl)ethyl]-3-{3-methyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 48hexaen-14-yl}urea (stereoisomer 1)rel-l-[(lR)-2-methoxy-l-(5-methylpyrimidin-2-yl)ethyl]-3-{3-methyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 49hexaen-14-yl}urea (stereoisomer 2)2-[5-(propan-2-yl)pyrimidin-2-yl]-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 5014-yl] acetamide2-(2-methyl- 1,3-oxazol-4-yl)-N- [(8R,9R)-3,8,9-trimethyl-7, 10-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 5114-yl] acetamiderel-l-[(lR)-3,3-difluoro-l-(5-methylpyrimidin-2-yl)propyl]-3-{3-methyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 52hexaen- 14-yl }urea (stereoisomer 2)rel-l-[(lR)-3,3-difluoro-l-(5-methylpyrimidin-2-yl)propyl]-3-{3-methyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 53hexaen-14-yl}urea (stereoisomer 1)N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 54 14-yl] -2- { 5- [( 1R*)- 1 -( 1 -methyl- 1 H-pyrazol-4-yl)ethyl]pyridin-2-yl } acetamide (stereoisomer 1)N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16]]octadeca-l(l l),2(6),4,12,14,17-hexaen- 55 14-yl] -2- { 5- [( 1R*)- 1 -( 1 -methyl- 1 H-pyrazol-4-yl)ethyl]pyridin-2-yl } acetamide(stereoisomer 2)2-[5-(2-hydroxypropan-2-yl)pyridin-2-yl]-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 56hexaen- 14-yl] acetamide2-{5H,6H,8H-imidazo[2,l-c][l,4]oxazin-2-yl}-N-[(8R,9R)-3,8,9-trimethyl-7,10- I- dioxa-3,4, 15,16-tetraazatetracyclo [9.7.0.0A{ 2,6 }.0A{ 12, 16 } ]octadeca- 571(11), 2(6), 4, 12, 14, 17 -hexaen- 14-yl] acetamide2-{5-[l-(difluoromethyl)cyclopropyl]pyridin-2-yl}-N-[(9R)-3,9-dimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 58hexaen- 14-yl]acetamide2-[l-(oxetan-3-yl)-lH-pyrazol-3-yl]-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17- 59hexaen- 14-yl] acetamideN-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 6014-yl] -2- { 5- [( 1R*)- 1 -(morpholin-4-yl)ethyl]pyridin-2-yl } acetamide (stereoisomer 1 ) N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 6114-yl]-2- { 5- [( 1 R*)- 1 -(morpholin-4-yl)ethyl]pyridin-2-yl } acetamide (stereoisomer 2) 2-{l-[(oxetan-3-yl)methyl]-lH-pyrazol-5-yl}-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 62hexaen- 14-yl]acetamide2-(l,2-dimethyl-lH-imidazol-4-yl)-N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 6314-yl]acetamide2-[4-(2-hydroxypropan-2-yl)-l,3-thiazol-2-yl]-N-[(8R,9R)-3,8,9-trimethyl-7,10- I- dioxa-3,4, 15,16-tetraazatetracyclo [9.7.0.0A{ 2,6 }.0A{ 12, 16 } ]octadeca- 641(11), 2(6), 4, 12, 14, 17 -hexaen- 14-yl] acetamide2-{l-[(oxetan-3-yl)methyl]-lH-pyrazol-3-yl}-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 65hexaen-14-yl]acetamide2-[l-methyl-5-(oxan-4-yl)-lH-pyrazol-3-yl]-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 66hexaen- 14-yl]acetamide2-(5-methyl-l,2,4-oxadiazol-3-yl)-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 6714-yl] acetamide2-[5-(2-hydroxypropan-2-yl)pyrazin-2-yl]-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 68hexaen- 14-yl]acetamide2-{5-[(2R*)-2-hydroxy-l-methoxypropan-2-yl]pyridin-2-yl]-N-[(8R,9R)-3,8,9- I- trimethyl-7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 69l(ll),2(6),4,12,14,17-hexaen-14-yl]acetamide (stereoisomer 2)2-{5-[(2R*)-2-hydroxy-l-methoxypropan-2-yl]pyridin-2-yl}-N-[(8R,9R)-3,8,9- I- trimethyl-7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca- 701(11), 2(6), 4,12, 14, 17 -hexaen- 14-yl] acetamide (stereoisomer 1)2-{5-methyl-4H,5H,6H,7H-[l,3]thiazolo[4,5-c]pyridin-2-yl}-N-[(8R,9R)-3,8,9- I- trimethyl-7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 711(11), 2(6), 4, 12, 14, 17 -hexaen- 14-yl] acetamide2-[(5R)-5-methyl-5H,6H,8H-imidazo[2,l-c][l,4]oxazin-2-yl]-N-[(8R,9R)-3,8,9- I- trimethyl-7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16]]octadeca- 721(11), 2(6), 4, 12, 14, 17 -hexaen- 14-yl] acetamide2-(5-{3-hydroxybicyclo[l.l.l]pentan-l-yl}pyridin-2-yl)-N-[(8R,9R)-3,8,9-trimethyl- I- 7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca- 731(11 ),2(6),4, 12,14, 17-hexaen- 14-yl](2H2)acetamide2-{5H,6H,8H,9H-imidazo[l,2-d][l,4]oxazepin-2-yl}-N-[(8R,9R)-3,8,9-trimethyl- I- 7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 741(11), 2(6), 4, 12, 14, 17 -hexaen- 14- y 1] acetamide2-{7-[(2R*)-l,l-difluoropropan-2-yl]-5H,6H,7H,8H-imidazo[l,2-a]pyrazin-2-yl}-N- I- [(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4, 15,16- 75 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16]]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl] acetamide (stereoisomer 2)2-{7-[(2R*)-l,l-difluoropropan-2-yl]-5H,6H,7H,8H-imidazo[l,2-a]pyrazin-2-yl}-N- I- [(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4,15,16- 76 tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(l 1), 2(6), 4,12, 14,17-hexaen- 14-yl] acetamide (stereoisomer 1)2-[5-(difluoromethyl)-l-methyl-lH-l,2,4-triazol-3-yl]-N-[(8R,9R)-3,8,9-trimethyl- I- 7,10-dioxa-3,4,l 5,16-tetraazatetracyclo[9.7.0.0A{ 2,6 },0A{ 12,16}]octadeca- 771(11), 2(6), 4, 12, 14, 17 -hexaen- 14- y 1] acetamide2-{ l-methyl-lH-pyrazolo[4,3-b]pyridin-5-yl}-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 78hexaen- 14-yl] acetamide2-{7-cyclopropyl-5H,6H,7H,8H-imidazo[l,2-a]pyrazin-2-yl}-N-[(8R,9R)-3,8,9- I- trimethyl-7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 791(11), 2(6), 4, 12, 14, 17 -hexaen- 14-yl] acetamide2- { 5- [(2R*)-2-methyl- 1,4-dioxan-2-yl]pyrimidin-2-yl } -N-[(8R,9R)-3,8,9-trimethyl- I- 7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16]]octadeca- 80l(ll),2(6),4,12,14,17-hexaen-14-yl]acetamide (stereoisomer 2)2-{5-[(2R*)-2-methyl-l,4-dioxan-2-yl]pyrimidin-2-yl}-N-[(8R,9R)-3,8,9-trimethyl- I- 7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 81l(ll),2(6),4,12,14,17-hexaen-14-yl]acetamide (stereoisomer 1)2-[(3R*)-3-(difluoromethyl)-lH,3H-furo[3,4-c]pyridin-6-yl]-N-[(8R,9R)-3,8,9- I- trimethyl-7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 821(11), 2(6), 4, 12, 14, 17 -hexaen- 14-yl] acetamide (stereoisomer 2)2-[(3R*)-3-(difluoromethyl)-lH,3H-furo[3,4-c]pyridin-6-yl]-N-[(8R,9R)-3,8,9- I- trimethyl-7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca- 831(11), 2(6), 4,12, 14, 17 -hexaen- 14-yl] acetamide (stereoisomer 1)2-[5-methyl-l-(oxetan-3-yl)-lH-imidazol-4-yl]-N-[(8R,9R)-3,8,9-trimethyl-7,10- I- dioxa-3,4, 15,16-tetraazatetracyclo [9.7.0.0A{ 2,6 }.0A{ 12, 16 } ]octadeca- 841(11), 2(6), 4, 12, 14, 17 -hexaen- 14-yl] acetamide2-[(6R*)-6-methyl-5H,6H,8H-imidazo[2,l-c][l,4]oxazin-2-yl]-N-[(8R,9R)-3,8,9- I- trimethyl-7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 85l(ll),2(6),4,12,14,17-hexaen-14-yl]acetamide (stereoisomer 2)2-[(6R*)-6-methyl-5H,6H,8H-imidazo[2,l-c][l,4]oxazin-2-yl]-N-[(8R,9R)-3,8,9- I- trimethyl-7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca- 86l(ll),2(6),4,12,14,17-hexaen-14-yl]acetamide (stereoisomer 1)2-[l-(2,2-difluoroethyl)-2-methyl-lH-imidazol-4-yl]-N-[(8R,9R)-3,8,9-trimethyl- I- 7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 871(11), 2(6), 4, 12, 14, 17 -hexaen- 14- y 1] acetamide2-{5-[(2R*)-2-methyloxetan-2-yl]pyrimidin-2-yl}-N-[(8R,9R)-3,8,9-trimethyl-7,10- I- dioxa-3,4, 15,16-tetraazatetracyclo [9.7,0.0A{ 2,6 }.0A{ 12, 16 } ]octadeca- 881 ( 11 ),2(6), 4, 12, 14, 17 -hexaen- 14-yl] acetamide (stereoisomer 2)2-{5-[(2R*)-2-methyloxetan-2-yl]pyrimidin-2-yl}-N-[(8R,9R)-3,8,9-trimethyl-7,10- I- dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca- 89l(ll),2(6),4,12,14,17-hexaen-14-yl]acetamide (stereoisomer 1)2-[6-oxo-5-(propan-2-yl)-4H,5H,6H,7H-pyrazolo[l,5-a]pyrazin-2-yl]-N-[(8R,9R)- I- 3,8,9-trimethyl-7,10-dioxa-3,4,15,16- 90 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl]acetamide2-{5',8'-dihydrospiro[cyclopropane-l,6'-imidazo[2,l-c][l,4]oxazin]-2'-yl}-N- I- [(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4,15,16- 91 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl] acetamide2-{5-methyl-4H,5H,6H,7H-pyrazolo[l,5-a]pyrazin-2-yl}-N-[(8R,9R)-3,8,9-trimethyl- I- 7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 921(11), 2(6), 4, 12, 14, 17 -hexaen- 14-yl] acetamide(lR*,2R*)-N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16]]octadeca-l(l l),2(6),4,12,14,17-hexaen- 9314-yl]-2-(5-methylpyrimidin-2-yl)cyclobutane-l -carboxamide (stereoisomer 2) (lR*,2R*)-N-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 9414-yl]-2-(5-methylpyrimidin-2-yl)cyclobutane- 1 -carboxamide (stereoisomer 1 ) 2-[(5S)-5-methyl-5H,6H,8H-imidazo[2,l-c][l,4]oxazin-2-yl]-N-[(8R,9R)-3,8,9- I- trimethyl-7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 951(11), 2(6), 4, 12, 14, 17 -hexaen- 14-yl] acetamide2-{5-[l-(difluoromethyl)cyclopropyl]pyrimidin-2-yl}-N-[(8R,9R)-3,8,9-trimethyl- I- 7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16]]octadeca- 961(11), 2(6), 4,12, 14, 17 -hexaen- 14-yl] acetamide2-{5-[(2R*)-l,l-difluoropropan-2-yl]pyrimidin-2-yl}-N-[(8R,9R)-3,8,9-trimethyl- I- 7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 97l(ll),2(6),4,12,14,17-hexaen-14-yl]acetamide (stereoisomer 2)2-{5-[(2R*)-l,l-difluoropropan-2-yl]pyrimidin-2-yl}-N-[(8R,9R)-3,8,9-trimethyl- I- 7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 98l(ll),2(6),4,12,14,17-hexaen-14-yl]acetamide (stereoisomer 1)2-{imidazo[l,2-a]pyrazin-2-yl}-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 9914-yl]acetamide2-( 1,2-dimethyl- 1 H-imidazol-4-yl)-N-[(8R,9R)-3,8,9-trimethyl-7, 10-dioxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 0014-yl] acetamide2-{5-[(2R*)-2-methyloxolan-2-yl]pyrimidin-2-yl}-N-[(8R,9R)-3,8,9-trimethyl-7,10- I- dioxa-3,4, 15,16-tetraazatetracyclo [9.7,0.0A{ 2,6 }.0A{ 12, 16 } ]octadeca- 011 ( 11 ),2(6), 4, 12, 14, 17 -hexaen- 14-yl] acetamide (stereoisomer 2)2-{5-[(2R*)-2-methyloxolan-2-yl]pyrimidin-2-yl}-N-[(8R,9R)-3,8,9-trimethyl-7,10- I- dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca- 02l(ll),2(6),4,12,14,17-hexaen-14-yl]acetamide (stereoisomer 1)2-{5-[(2R*)-2-methyl-l,4-dioxan-2-yl]pyridin-2-yl}-N-[(8R,9R)-3,8,9-trimethyl- I- 7, 10-dioxa- 3,4, 15, 16-tetraazatetracyclo [9.7,0.0A{ 2,6 },0A{ 12, 16 }]octadeca- 03l(ll),2(6),4,12,14,17-hexaen-14-yl]acetamide (stereoisomer 2)2-{5-[(2R*)-2-methyl-l,4-dioxan-2-yl]pyridin-2-yl}-N-[(8R,9R)-3,8,9-trimethyl- I- 7, 10-dioxa- 3,4, 15, 16-tetraazatetracyclo [9.7,0.0A{ 2,6 },0A{ 12, 16 }]octadeca- 04l(ll),2(6),4,12,14,17-hexaen-14-yl]acetamide (stereoisomer 1)2-(5-{3-fluorobicyclo[l.l.l]pentan-l-yl}pyrimidin-2-yl)-N-[(8R,9R)-3,8,9-trimethyl- I- 7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 051(11 ), 2(6), 4,12,14,17-hexaen-l 4-yl]acetamide2-[5-(l-hydroxycyclopropyl)pyridin-2-yl]-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 06hexaen- 14-yl]acetamide2-{5-[(lR*)-l-cyclopropyl-l-hydroxyethyl]-l-methyl-lH-pyrazol-3-yl}-N-[(8R,9R)- I- 3,8,9-trimethyl-7,10-dioxa-3,4,15,16- 07 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl] acetamide (stereoisomer 2)2- { 5 -[( 1 R*)- 1 -cyclopropyl- 1 -hydroxyethyl] - 1 -methyl- 1 H-pyrazol-3-yl } -N- [(8R,9R)- I- 3,8,9-trimethyl-7,10-dioxa-3,4,15,16- 08 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen-14-yl]acetamide (stereoisomer 1)2-[5-methyl-l-(propan-2-yl)-lH-l,2,4-triazol-3-yl]-N-[(8R,9R)-3,8,9-trimethyl-7,10- I- dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 091(11), 2(6), 4,12, 14, 17 -hexaen- 14-yl] acetamideN-[(9R)-3,9-dimethyl-7,10-dioxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 10 14-yl] -2-( 1 - { 6-fluoroimidazo[ 1,2-a]pyridin-3-yl } -5-methyl- 1 H-pyrazol-3- yl)acetamide2-[5-(4-hydroxyoxan-4-yl)pyridin-2-yl]-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 11hexaen- 14-yl] acetamide2-{5-[(2R*)-l,l-difluoro-2-hydroxypropan-2-yl]pyridin-2-yl}-N-[(8R,9R)-3,8,9- I- trimethyl-7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 121(1 l),2(6),4,12,14,17-hexaen-14-yl]acetamide (stereoisomer 2)2-{5-[(2R*)-l,l-difluoro-2-hydroxypropan-2-yl]pyridin-2-yl}-N-[(8R,9R)-3,8,9- I- trimethyl-7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 13l(ll),2(6),4,12,14,17-hexaen-14-yl]acetamide (stereoisomer 1)N-[(9R)-3,9-dimethyl- 10-oxa-3,4, 15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16]]octadeca-l(l l),2(6),4,12,14,17-hexaen- 1414-yl]-2-[5-(2-hydroxypropan-2-yl)pyridin-2-yl]acetamideN- { 9,9-difluoro-3-methyl-7, 11 -dioxa-3,4, 16,17- I- tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca-l(12),2(6),4,13,15,18-hexaen- 1515-yl}-2-[5-(2-hydroxypropan-2-yl)pyridin-2-yl]acetamide2-[(7R*)-7-hydroxy-7-methyl-5H,6H,7H-cyclopenta[c]pyridin-3-yl]-N-[(8R,9R)- I- 3,8,9-trimethyl-7, 10-dioxa-3,4, 15,16- 16 tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l (11 ), 2(6), 4,12,14,17 -hexaen - 14-yl] acetamide (stereoisomer 2)2-[(7R*)-7-hydroxy-7-methyl-5H,6H,7H-cyclopenta[c]pyridin-3-yl]-N-[(8R,9R)- I- 3,8,9-trimethyl-7, 10-dioxa-3,4, 15,16- 17 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16]]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl] acetamide (stereoisomer 1)2-{5-[(lR*)-l-hydroxyethyl]pyridin-2-yl}-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 18hexaen-14-yl]acetamide (stereoisomer 2)2-{5-[(lR*)-l-hydroxyethyl]pyridin-2-yl}-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 19hexaen-14-yl]acetamide (stereoisomer 1)2-[5-(4-cyanooxan-4-yl)pyridin-2-yl]-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 20hexaen- 14-yl]acetamide2- [5-( 1,4-dimethyl- 1 H-pyrazol-5 -yl)pyridin-2-yl] -N- [(8R,9R)-3, 8,9 -trimethyl-7, 10- I- dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 211(11), 2(6), 4, 12, 14, 17 -hexaen- 14- y 1] acetamide2-{7-methyl-5H,6H,7H,8H-imidazo[l,2-a]pyrazin-2-yl}-N-[(8R,9R)-3,8,9-trimethyl- I- 7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16]]octadeca- 221(11), 2(6), 4,12, 14, 17 -hexaen- 14-yl] acetamide2-{5-[(lR*)-2,2,2-trifluoro-l-hydroxyethyl]pyridin-2-yl}-N-[(8R,9R)-3,8,9-trimethyl- I- 7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 23l(ll),2(6),4,12,14,17-hexaen-14-yl]acetamide (stereoisomer 2)2-{5-[(lR*)-2,2,2-trifluoro-l-hydroxyethyl]pyridin-2-yl}-N-[(8R,9R)-3,8,9-trimethyl- I- 7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 24l(ll),2(6),4,12,14,17-hexaen-14-yl]acetamide (stereoisomer 1)2-[5-(difluoromethoxy)pyridin-2-yl]-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17- 25hexaen- 14-yl]acetamide2-[5-(l-hydroxycyclobutyl)pyridin-2-yl]-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 26hexaen- 14-yl]acetamideN-[(9R)-3,9-dimethyl-10-oxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 2714-yl] -2- [5 -( 1 -hydroxycyclopropyl)pyridin-2-yl]acetamide2-{5H,6H,8H-[l,2,4]triazolo[3,2-c][l,4]oxazin-2-yl}-N-[(8R,9R)-3,8,9-trimethyl- I- 7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16]]octadeca- 281 (11 ), 2(6), 4, 12, 14, 17 -hexaen- 14- yl] acetamide2-{5',7'-dihydrospiro[cyclopropane-l,6'-pyrrolo[l,2-a]imidazol]-2'-yl}-N-[(8R,9R)- I- 3,8,9-trimethyl-7, 10-dioxa-3,4, 15,16- 29 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl] acetamide2-[(8R*)-8-methyl-5H,6H,8H-imidazo[2,l-c][l,4]oxazin-2-yl]-N-[(8R,9R)-3,8,9- I- trimethyl-7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 30l(ll),2(6),4,12,14,17-hexaen-14-yl]acetamide (stereoisomer 1)2-[(8R*)-8-methyl-5H,6H,8H-imidazo[2,l-c][l,4]oxazin-2-yl]-N-[(8R,9R)-3,8,9- I- trimethyl-7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca- 31l(ll),2(6),4,12,14,17-hexaen-14-yl]acetamide (stereoisomer 2)2- { 5- [(4s)-2-oxabicyclo[2.1.1 ]hexan-4-yl]pyrimidin-2-yl } -N- [(8R,9R)-3,8,9- I- trimethyl-7, 10-dioxa-3,4, 15,16-tetraazatetracyclo[9.7.0.0A{ 2,6 },0A{ 12, 16 } ]octadeca- 321 (11 ), 2(6), 4, 12, 14, 17 -hexaen- 14-yl] acetamide2-{7-cyclopropyl-5H,6H,7H,8H-imidazo[l,2-a]pyrazin-2-yl}-N-[(9R)-3,9-dimethyl- I- 7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 331(11), 2(6), 4, 12, 14, 17 -hexaen- 14-yl] acetamide2-[5-methyl-l-(oxetan-3-yl)-lH-l,2,4-triazol-3-yl]-N-[(8R,9R)-3,8,9-trimethyl-7,10- I- dioxa-3,4, 15,16-tetraazatetracy clo [9.7,0.0A{ 2,6 }.0A{ 12, 16 } ]octadeca- 341(11), 2(6), 4, 12, 14, 17 -hexaen- 14-yl] acetamide2-{5',8'-dihydrospiro[cyclopropane-l,6'-imidazo[2,l-c][l,4]oxazin]-2'-yl}-N-[(9R)- I- 3,9-dimethyl-7, 10-dioxa-3,4, 15,16- 35 tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen-14-yl] acetamide2-{ l-[(lR*)-2,2-difluorocyclopropyl]-2-methyl-lH-imidazol-4-yl}-N-[(8R,9R)-3,8,9- I- trimethyl-7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca- 36l(ll),2(6),4,12,14,17-hexaen-14-yl]acetamide (stereoisomer 1)2- { 1 - [( 1 R*)-2,2-difluorocyclopropyl]-2-methyl- 1 H-imidazol-4-yl } -N- [(8R,9R)-3,8,9- I- trimethyl-7, 10-dioxa-3,4, 15,16-tetraazatetracyclo[9.7.0.0A{ 2,6 },0A{ 12, 16 } ]octadeca- 37l(ll),2(6),4,12,14,17-hexaen-14-yl]acetamide (stereoisomer 2)(lS,2R)-2-[5-(difluoromethyl)pyridin-2-yl]-N-[(8R*)-3-methyl-8- I- [(methylsulfanyl)methyl] -7, 10-dioxa-3,4, 15,16- 38 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16]]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl]cyclopropane-l -carboxamide (stereoisomer 1)(lS,2R)-2-[5-(difluoromethyl)pyridin-2-yl]-N-[(8R*)-3-methyl-8- I- [(methylsulfanyl)methyl] -7, 10-dioxa-3,4, 15,16- 39 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl]cyclopropane-l -carboxamide (stereoisomer 2)N-[(9R)-3,9-dimethyl-10-oxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 4014-yl]-2-{7-methyl-5H,6H,7H,8H-imidazo[l,2-a]pyrazin-2-yl}acetamideN-[(9R)-3,9-dimethyl-10-oxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 4114-yl]-2-{5H,6H,8H,9H-imidazo[l,2-d][l,4]oxazepin-2-yl}acetamide2-{2-methyl-2H-pyrazolo[4,3-b]pyridin-5-yl}-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17- 42hexaen- 14-yl] acetamide2-(5-methyl-6-oxo-5,6,7,8-tetrahydro-l,5-naphthyridin-2-yl)-N-[(8R,9R)-3,8,9- I- trimethyl-7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 431(11), 2(6), 4, 12, 14, 17 -hexaen- 14-yl] acetamide(lS,2R)-N-[(9R*)-3-methyl-9-(methylsulfanyl)-7,ll-dioxa-3,4,16,17- I- tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca-l(12),2(6),4,13,15,18-hexaen- 4415-yl]-2-(5-methylpyrimidin-2-yl)cyclopropane-l-carboxamide (stereoisomer 2) (lS,2R)-N-[(9R*)-3-methyl-9-(methylsulfanyl)-7,ll-dioxa-3,4,16,17- I- tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca-l(12),2(6),4,13,15,18-hexaen- 4515-yl]-2-(5-methylpyrimidin-2-yl)cyclopropane-l-carboxamide (stereoisomer 1) 2-{7'-methyl-7',8'-dihydro-5'H-spiro[cyclopropane-l,6'-imidazo[l,2-a]pyrazin]-2'-yl}- I- N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4,15,16- 46 tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl] acetamide2-[5-(2-hydroxypropan-2-yl)-l,3-oxazol-2-yl]-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 47hexaen-14-yl]acetamideN-[(9R)-3,9-dimethyl-10-oxa-3,4,15,16- I- tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 4814-yl]-2-[7-(oxetan-3-yl)-5H,6H,7H,8H-imidazo[l,2-a]pyrazin-2-yl]acetamide 2-[5-(cyclopropanesulfonyl)pyridin-2-yl]-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16]]octadeca-l(ll),2(6),4,12,14,17- 49hexaen- 14-yl] acetamide2-{7-ethyl-5H,6H,7H,8H-imidazo[l,2-a]pyrazin-2-yl}-N-[(8R,9R)-3,8,9-trimethyl- I- 7, 10-dioxa-3,4, 15,16-tetraazatetracyclo [9.7,0.0A{ 2,6 },0A{ 12, 16 } ]octadeca- 501(11), 2(6), 4, 12, 14, 17 -hexaen- 14-yl] acetamide(1 S,2R)-N- { 3-methyl- 11 -oxa-7-thia-3,4, 16,17- I- tetraazatetracyclo[10.7.0.0A{2,6}.0A{13,17}]nonadeca-l(12),2(6),4,13,15,18-hexaen- 5115-yl}-2-(5-methylpyrimidin-2-yl)cyclopropane-l -carboxamide2-[8-oxo-7-(propan-2-yl)-5H,6H,7H,8H-imidazo[l,2-a]pyrazin-2-yl]-N-[(8R,9R)- I- 3,8,9-trimethyl-7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.520A{ 12, 16 } ]octadeca- 1 ( 11 ), 2(6),4, 12, 14, 17-hexaen- 14-yl] acetamide( 1 S,2R)-N- { 3-methyl-7-oxa- 11 -thia-3,4, 16, 17- I- tetraazatetracyclo [ 10.7.0.0A{ 2, 6 }.0A{ 13, 17 } ]nonadeca- 1(12), 2(6), 4, 13, 15,18-hexaen- 5315-yl}-2-(5-methylpyrimidin-2-yl)cyclopropane-l -carboxamide2-{7-[(4-methyl-l,3-oxazol-2-yl)methyl]-5H,6H,7H,8H-imidazo[l,2-a]pyrazin-2-yl}- I- N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4,15,16- 54 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl] acetamide2-{7-cyclopropanecarbonyl-5H,6H,7H,8H-imidazo[l,2-a]pyrazin-2-yl}-N-[(8R,9R)- I- 3,8,9-trimethyl-7,10-dioxa-3,4,15,16- 55 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16]]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl] acetamide2-{5-[(3S,3aR,6aR)-hexahydrofuro[3,2-b]furan-3-yl]pyrimidin-2-yl}-N-[(8R,9R)- I- 3,8,9-trimethyl-7, 10-dioxa-3,4, 15,16- 56 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl] acetamide2-{5-methyl-4H,5H,6H,7H-[l,3]oxazolo[4,5-c]pyridin-2-yl}-N-[(8R,9R)-3,8,9- I- trimethyl-7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 571(11), 2(6), 4, 12, 14, 17 -hexaen- 14-yl] acetamide2-[(2S)-5',7'-dihydrospiro[oxetane-2,6'-pyrrolo[l,2-a]imidazol]-2'-yl]-N-[(8R,9R)- I- 3,8,9-trimethyl-7,10-dioxa-3,4,15,16- 58 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl] acetamide2-[(2R)-5',7'-dihydrospiro[oxetane-2,6'-pyrrolo[l,2-a]imidazol]-2'-yl]-N-[(8R,9R)- I- 3,8,9-trimethyl-7, 10-dioxa-3,4, 15,16- 59 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl] acetamide2-{5,8-dihydrospiro[[l,2,4]triazolo[3,2-c][l,4]oxazine-6,r-cyclopropan]-2-yl}-N- I- [(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4,15,16- 60 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16]]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl]acetamide2-{7-methyl-7,8-dihydro-5H-spiro[[l,2,4]triazolo[l,5-a]pyrazine-6,l'-cyclopropan]-2- I- yl}-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4,15,16- 61 tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl] acetamide2-[(3S,5S)-l,8-diazatricyclo[5.3.0.0A{3,5]]deca-7,9-dien-9-yl]-N-[(8R,9R)-3,8,9- I- trimethyl-7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 621 ( 11 ), 2(6), 4, 12, 14, 17 -hexaen- 14-yl] acetamide2-{5-[(3R,3aR,6aR)-hexahydrofuro[3,2-b]furan-3-yl]pyrimidin-2-yl}-N-[(8R,9R)- I- 3,8,9-trimethyl-7, 10-dioxa-3,4, 15,16- 63 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl] acetamide2-{7-[(lR)-2,2-difluorocyclopropyl]-5H,6H,7H,8H-imidazo[l,2-a]pyrazin-2-yl}-N- I- [(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4,15,16- 64 tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl] acetamide2-{7-cyclopropyl-5H,6H,7H,8H-[l,2,4]triazolo[l,5-a]pyrazin-2-yl}-N-[(8R,9R)- I- 3,8,9-trimethyl-7,10-dioxa-3,4,15,16- 65 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl] acetamide2-[(5R)-5-hydroxy-5-methyl-4H,5H,6H-cyclopenta[d][l,3]oxazol-2-yl]-N-[(8R,9R)- I- 3,8,9-trimethyl-7, 10-dioxa-3,4, 15,16- 66 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl]acetamide2-{5H,6H,8H-imidazo[4,3-c][l,4]oxazin-l-yl}-N-[(8R,9R)-3,8,9-trimethyl-7,10- I- dioxa-3,4, 15,16-tetraazatetracyclo [9.7,0.0A{ 2,6 }.0A{ 12, 16 } ]octadeca- 671(11), 2(6), 4, 12, 14, 17 -hexaen- 14-yl] acetamide2-[(5R)-5-hydroxy-5-methyl-4H,5H,6H-cyclopenta[d][l,3]thiazol-2-yl]-N-[(8R,9R)- I- 3,8,9-trimethyl-7, 10-dioxa-3,4, 15,16- 68 tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl] acetamide2-(l,3-dimethyl-lH-l,2,4-triazol-5-yl)-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 69hexaen- 14-yl] acetamide(3S)-3-hydroxy-3-(5-methylpyrimidin-2-yl)-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17- 70hexaen- 14-yl]butanamide(3R)-3-hydroxy-3-(5-methylpyrimidin-2-yl)-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa- I- 3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16]]octadeca-l(ll),2(6),4,12,14,17- 71hexaen- 14-yl]butanamide2- { 1 -methyl-5- [(3r)-3-hydroxy-3-methylcyclobutyl]- 1 H- 1,2,4-triazol-3-yl } -N- I- [(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4,15,16- 72 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl] acetamide2- { 1 -methyl-5- [(3s)-3-hydroxy-3-methylcyclobutyl]- 1 H- 1,2,4-triazol-3-yl } -N- I- [(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4, 15,16- 73 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl] acetamide2-[(5S)-5-hydroxy-5-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl]-N-[(8R,9R)-3,8,9- I- trimethyl-7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca- 741(11), 2(6), 4, 12, 14, 17 -hexaen- 14-yl] acetamide2-[(5R)-5-hydroxy-5-methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl]-N-[(8R,9R)-3,8,9- I- trimethyl-7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 751 ( 11 ), 2(6), 4, 12, 14, 17 -hexaen- 14-yl] acetamide2-{5-[(3R,3aR,6R,6aR)-6-hydroxy-hexahydrofuro[3,2-b]furan-3-yl]pyrimidin-2-yl}- I- N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4,15,16- 76 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl] acetamide2-{5-[(3R,3aR,6S,6aR)-6-hydroxy-hexahydrofuro[3,2-b]furan-3-yl]pyrimidin-2-yl}- I- N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4,15,16- 77 tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl] acetamide2-[(6R)-6-hydroxy-6-methyl-4,5,6,7-tetrahydro-l,3-benzoxazol-2-yl]-N-[(8R,9R)- I- 3,8,9-trimethyl-7,10-dioxa-3,4,15,16- 78 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl] acetamide2-[(6S)-6-hydroxy-6-methyl-4,5,6,7-tetrahydro-l,3-benzoxazol-2-yl]-N-[(8R,9R)- I- 3,8,9-trimethyl-7, 10-dioxa-3,4, 15,16- 79 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl]acetamide2-[(5S)-5-hydroxy-5-methyl-4,5,6,7-tetrahydro-2H-l,2,3-benzotriazol-2-yl]-N- I- [(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4, 15,16- 80 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16]]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl] acetamide2-[(5R)-5-hydroxy-5-methyl-4,5,6,7-tetrahydro-2H-l,2,3-benzotriazol-2-yl]-N- I- [(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4,15,16- 81 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl] acetamide2-{7-[(lS)-2,2-difluorocyclopropyl]-5H,6H,7H,8H-[l,2,4]triazolo[l,5-a]pyrazin-2- I- yl}-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4,15,16- 82 tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl] acetamide2-{7-[(lR)-2,2-difluorocyclopropyl]-5H,6H,7H,8H-[l,2,4]triazolo[l,5-a]pyrazin-2- I- yl}-N-[(8R,9R)-3,8,9-trimethyl-7,10-dioxa-3,4,15,16- 83 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl] acetamide2-[(6R)-6-(difluoromethyl)-5H,6H,7H-pyrrolo[l,2-b][l,2,4]triazol-2-yl]-N-[(8R,9R)- I- 3,8,9-trimethyl-7, 10-dioxa-3,4, 15,16- 84 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen- 14-yl]acetamide2-[(5S)-5-hydroxy-5-methyl-2H,4H,5H,6H-cyclopenta[c]pyrazol-2-yl]-N-[(8R,9R)- I- 3,8,9-trimethyl-7, 10-dioxa-3,4, 15,16- 85 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16]]octadeca-l(l l),2(6),4,12,14,17-hexaen- 14-yl] acetamide2-[(5R)-5-hydroxy-5-methyl-2H,4H,5H,6H-cyclopenta[c]pyrazol-2-yl]-N-[(8R,9R)- I- 3,8,9-trimethyl-7, 10-dioxa-3,4, 15,16- 86 tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca-l(ll),2(6),4,12,14,17-hexaen-14-yl] acetamide2-{3,7-dimethyl-5H,6H,7H,8H-imidazo[l,2-a]pyrazin-2-yl}-N-[(8R,9R)-3,8,9- I- trimethyl-7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{ 12,16}]octadeca- 871(11), 2(6), 4,12, 14, 17 -hexaen- 14-yl] acetamide2- { 7-methyl-5H,6H,7H,8H-imidazo[ 1,5-a]pyrazin- 1 -yl } -N- [(8R,9R)-3,8,9-trimethyl- I- 7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 881(11), 2(6), 4, 12, 14, 17 -hexaen- 14-yl] acetamide(3S)-3-hydroxy-3-{5H,6H,8H-imidazo[2,l-c][l,4]oxazin-2-yl}-N-[(8R,9R)-3,8,9- I- trimethyl-7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6].0A{12,16]]octadeca- 891 ( 11 ),2(6), 4, 12, 14, 17 -hexaen- 14-yl]butanamide(3R)-3-hydroxy-3-{5H,6H,8H-imidazo[2,l-c][l,4]oxazin-2-yl}-N-[(8R,9R)-3,8,9- I- trimethyl-7,10-dioxa-3,4,15,16-tetraazatetracyclo[9.7.0.0A{2,6}.0A{12,16}]octadeca- 901 ( 11 ), 2(6), 4, 12, 14, 17 -hexaen- 14- yl]butanamide2-(5-hydroxy-5-methyl-5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl)-N-((2R,3R)-2,3,7- I- trimethyl-2,3-dihydro-7H-pyrazolo[l,5-a]pyrazolo[3',4':7,8][l,4]dioxocino[5,6- 91c]pyridin-12-yl)acetamide(R*)-3-hydroxy-3-(5-methylpyrimidin-2-yl)-N-((2R,3R)-2,3,7-trimethyl-2,3-dihydro- I- 7H-pyrazolo[l,5-a]pyrazolo[3',4':7,8][l,4]dioxocino[5,6-c]pyridin-12-yl)butanamide 92(stereoisomer 2)(R*)-3-hydroxy-3-(5-methylpyrimidin-2-yl)-N-((2R,3R)-2,3,7-trimethyl-2,3-dihydro- I- 7H-pyrazolo[l,5-a]pyrazolo[3',4':7,8][l,4]dioxocino[5,6-c]pyridin-12-yl)butanamide 93(stereoisomer 1)2-(7-(2,2-difluoroethyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazin-2-yl)-N-((2R,3R)- I- 2,3,7-trimethyl-2,3-dihydro-7H-pyrazolo[l,5-a]pyrazolo[3',4':7,8][l,4]dioxocino[5,6- 94c]pyridin-12-yl)acetamideN-(6,6-difluoro-ll-methyl-6,7-dihydro-5H,llH-pyrazolo[l,5- I- a]pyrazolo[3',4':8,9][l,5]dioxonino[6,7-c]pyridin-2-yl)-2-(7-methyl-5, 6,7,8- 95tetrahydroimidazo[1,2-a]pyrazin-2-yl)acetamide2-(7-ethyl-5,6,7,8-tetrahydroimidazo[l,2-a]pyrazin-2-yl)-N-((2aS,13aR)-6-methyl- I- l,2,2a,13a-tetrahydro-6H-cyclobuta[2,3]pyrazolo[3',4':7,8][l,4]dioxocino[5,6- 96c]pyrazolo[ 1,5-a]pyridin- 1 l-yl)acetamideN-(6,6-difluoro-ll-methyl-6,7-dihydro-5H,llH-pyrazolo[l,5- I- a]pyrazolo[3',4':8,9][l,5]dioxonino[6,7-c]pyridin-2-yl)-2-(7-ethyl-5, 6,7,8- 97tetrahydroimidazo[l,2-a]pyrazin-2-yl)acetamide2-(5'-methyl-6'-oxo-5',8'-dihydro-6'H-spiro[cyclopropane-l,7'-pyrido[2,3-b]pyrazin]- I- 2'-yl)-N-((2R,3R)-2,3,7-trimethyl-2,3-dihydro-7H-pyrazolo[l,5- 98a]pyrazolo[3',4':7,8][l,4]dioxocino[5,6-c]pyridin-12-yl)acetamide2-(l-methyl-2-oxo-l,4-dihydro-2H-pyrido[3,2-d][l,3]oxazin-6-yl)-N-((2R,3R)-2,3,7- I- trimethyl-2,3-dihydro-7H-pyrazolo[l,5-a]pyrazolo[3',4':7,8][l,4]dioxocino[5,6- 99c]pyridin- 12-yl)acetamide2-((5aR,6aR)-5a,6,6a,7-tetrahydro-5H-cyclopropa[d]imidazo[l,2-a]pyridin-2-yl)-N- I- ((2R,3R)-2,3,7-trimethyl-2,3-dihydro-7H-pyrazolo[l,5- 00a]pyrazolo[3',4':7,8][l,4]dioxocino[5,6-c]pyridin-12-yl)acetamide (stereoisomer 2)

[0228] In some embodiments, the present invention provides a compound set forth in Table 1, above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound set forth in Table 1, above.

[0229] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound disclosed herein (described in embodiments herein, both singly and in combination), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent. For example, in some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula I as defined above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula I as defined above, together with a pharmaceutically acceptable carrier, excipient, or diluent. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound set forth in Table 1 above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound set forth in Table 1 above, together with a pharmaceutically acceptable carrier, excipient, or diluent.4. General Methods of Providing the Present Compounds

[0230] The compounds of this invention may be prepared or isolated in general by synthetic and / or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples, herein.5. Uses, Formulation and AdministrationPharmaceutically acceptable compositions

[0231] According to another embodiment, the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In certain embodiments, the amount of compound in compositions of this invention is such that is effective to measurably inhibit SIK2, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a compositionof this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient.

[0232] The term “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.

[0233] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, poly acrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0234] A “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitory active metabolite or residue thereof.

[0235] As used herein, the term "active metabolite or residue thereof" means that a metabolite or residue thereof is also an inhibitor of SIK2, or a mutant thereof.

[0236] The subject matter disclosed herein includes prodrugs, metabolites, derivatives, and pharmaceutically acceptable salts of compounds of the invention. Metabolites include compounds produced by a process comprising contacting a compound of the invention with a mammal for a period of time sufficient to yield a metabolic product thereof. If the compound of the invention is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citricacid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p -toluenesulfonic acid or ethanesulfonic acid, or the like. If the compound of the invention is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0237] A compound of the invention can be in the form of a "prodrug," which includes compounds with moieties which can be metabolized in vivo. Generally, the prodrugs are metabolized in vivo by esterases or by other mechanisms to active drugs. Examples of prodrugs and their uses are well known in the art (See, e.g., Berge et al. (1977) " Pharmaceutical Salts", J. Pharm. Sci. 66:1-19). The prodrugs can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent. Hydroxyl groups can be converted into esters via treatment with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted, branch or unbranched lower alkyl ester moieties, (e.g., propionic acid esters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetyloxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower-alkyl amides, di-lower alkyl amides, and hydroxy amides. Prodrugs which are converted to active forms through other mechanisms in vivo are also included. In aspects, the compounds of the invention are prodrugs of any of the formulae herein.

[0238] Compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally orintravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0239] For this purpose, any bland fixed oil may be employed 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 versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0240] Injectable formulations can be sterilized, for example, by filtration through a bacterial-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 prior to use.

[0241] 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 may 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 then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers includepoly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0242] Alternatively, pharmaceutically acceptable compositions of this 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 will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0243] Pharmaceutically acceptable compositions of this invention may also be administered topically, especially 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.

[0244] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0245] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components 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.

[0246] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage formscan be made by dissolving or dispensing the compound in the proper 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 by dispersing the compound in a polymer matrix or gel.

[0247] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[0248] Pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0249] Most preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.

[0250] Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0251] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid,b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar--agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0252] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of 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 formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0253] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of 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 formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of theintestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0254] 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 compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0255] The compounds of this invention, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Implantable devices coated with a compound of this invention are another embodiment of the present invention.

[0256] The amount of compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 and 100 mg / kg, 0.01 and 50 mg / kg, or 1 and 25 mg / kg, body weight / day of the compound can be administered to a patient receiving these compositions.

[0257] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.

[0258] Compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.4. Uses of Compounds and Pharmaceutically Acceptable Compositions

[0259] Compounds and compositions described herein are generally useful for the inhibition of kinase activity of one or more enzymes. In some embodiments the kinase inhibited by the compounds and methods of the invention is SIK2

[0260] The presently disclosed compounds find use in inhibiting SIK2 protein kinase. In one embodiment, the subject matter disclosed herein is directed to a method of inhibiting SIK2, the method comprising contacting SIK2 with an effective amount of a compound of the invention or a pharmaceutical composition described herein.

[0261] The presently disclosed compounds can be used in a method for inhibiting SIK2. Such methods comprise contacting SIK2 with an effective amount of a presently disclosed compound. By "contact" is intended bringing the compound within close enough proximity to an isolated SIK2 kinase or a cell expressing SIK2 such that the compound is able to bind to and inhibit the SIK2. The compound can be contacted with SIK2 in vitro or in vivo via administration of the compound to a subject.

[0262] In one aspect, provided herein is a method of inhibiting SIK2 in a biological sample. The method comprises contacting the sample with a compound disclosed herein (such as a compound of formula I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (such as a composition comprising a compound disclosed herein [such as a compound of formula I] and a pharmaceutically acceptable carrier, adjuvant, or vehicle). The term “biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[0263] Any method known in the art to measure the kinase activity of SIK2 may be used to determine if SIK2 has been inhibited, including in vitro assays, immunoblots with antibodiesspecific for phosphorylated targets of SIK2, or the measurement of a downstream biological effect of SIK2 kinase activity.

[0264] Provided herein are compounds and pharmaceutical compositions that inhibit SIK2 protein kinase, as well as methods of treatment using such compounds and pharmaceutical compositions. The compounds and compositions can be used in methods of modulating the immune system, for treatment of diseases, and for treatment of cells in vivo, in vitro, or ex vivo.

[0265] The present disclosure provides methods of inhibiting SIK2 in a patient. The method comprises administering to a patient a compound disclosed herein (such as a compound of formula I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (such as a composition comprising a compound disclosed herein [such as a compound of formula I] and a pharmaceutically acceptable carrier, adjuvant, or vehicle).

[0266] The presently disclosed compounds can be used to treat a SIK2-mediated disorder. As used herein, a " SIK2-mediated disorder" is a pathological condition in which SIK2 activity is necessary for the genesis or maintenance of the pathological condition.

[0267] Accordingly, in one aspect, provided herein is a method of treating a SIK2-mediated disorder, disease, or condition in a patient. The method comprises administering to said patient a compound disclosed herein (such as a compound of formula I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (such as a composition comprising a compound disclosed herein [such as a compound of formula I] and a pharmaceutically acceptable carrier, adjuvant, or vehicle). In some embodiments, the present invention provided a compound disclosed herein (such as a compound of formula I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein for use in medicine.

[0268] In some embodiments, the SIK2-mediated disorder is selected from inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of TNFα, interferons, IL-6, IL- 12 and / or IL-23, respiratory diseases, endocrine and / or metabolic diseases, cardiovascular diseases, dermatological diseases, and abnormal angiogenesis associated diseases.

[0269] In some embodiments, the present invention provides a method of treating an inflammatory disease in a patient in need thereof, wherein the method comprises administering to the patient acompound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0270] In some embodiments, the present invention provides a method of treating an autoinflammatory disease in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0271] In some embodiments, the present invention provides a method of treating an autoimmune disease in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0272] In some embodiments, the present invention provides a method of treating cancer in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is selected from solid tumors (e.g., bone cancer, skin cancer, prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, kidney cancer, bladder cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, bile duct cancer, bladder cancer), hematological cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma or multiple myeloma) and combinations of said cancers.

[0273] In some embodiments, the SIK2-mediated disorder is a cancer selected from ovarian cancer, breast cancer, acute myeloid leukemia, and multiple myeloma.

[0274] In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is a solid tumor cancer. In some embodiments, the cancer is lung cancer, non-small cell lung cancer (NSCLC), bone cancer, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, colorectal cancer, anal cancer, stomach cancer, colon cancer, breast cancer, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin’s Disease, hepatocellular cancer, cancer of the esophagus,cancer of the small intestine, cancer of the endocrine system (e.g., cancer of the thyroid, pancreas, parathyroid or adrenal glands), sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer, hormone-refractory prostate cancer, bladder cancer, kidney cancer, renal cell carcinoma, carcinoma of the renal pelvis, pediatric malignancy, neoplasms of the central nervous system, primary CNS lymphoma, spinal axis tumors, medulloblastoma, brain stem gliomas, or pituitary adenomas. In some embodiments, the cancer is a liquid tumor cancer. In some embodiments, the cancer is a leukemia. In some embodiments, the leukemia is acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), or chronic myelogenous leukemia (CML). In some embodiments, the cancer is a lymphoma. In some embodiments, the lymphoma is small lymphocytic lymphoma (SLL), cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, or Waldenstrom macroglobulinemia.

[0275] In yet another embodiment, provided herein are methods for treating diseases or disorders selected from the group consisting of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFα, interferons, IL- 12 and / or IL-23, respiratory diseases, endocrine and / or metabolic diseases, cardiovascular diseases, dermatological diseases, and abnormal angiogenesis associated diseases, in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, or a pharmaceutical composition described herein.

[0276] In some embodiments, the disease or disorder is an inflammatory disease. In some embodiments, the inflammatory disease is rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g., asthma), chronic obstructive pulmonary disease (COPD), or inflammatory bowel diseases (e.g., Crohn’s disease, ulcerative colitis).

[0277] In some embodiments, the disease or disorder is an autoinflammatory disease. In some embodiments, the autoinflammatory disease is Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF), tumor necrosis factor receptor-associated periodicsyndrome (TRAPS), Behcet’s disease, Systemic-onset Juvenile Idiopathic Arthritis (SJIA), Still’s disease, hemophagocytic lymphohistiocytosis, or macrophage activation syndrome.

[0278] In other embodiments, the present invention also provides methods for improving, restoring or enhancing fertility and for increasing oocyte production in a female subject by administering to the female subject an effective amount of a compound described herein, or a pharmaceutically acceptable salt, or stereoisomer thereof, or a pharmaceutical composition described herein.

[0279] In some embodiments, the disease or disorder is an autoimmune disease. In some embodiments, the autoimmune disease is COPD, asthma, bronchitis, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjogren’s syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g., Crohn’s disease and ulcerative colitis), atherosclerosis, or amyotrophic lateral sclerosis.

[0280] In some embodiments, the disease or disorder is a proliferative disease. In some embodiments, the proliferative disease is cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma, or fibrosis.

[0281] In some embodiments, the disease or disorder is a fibrotic disease. In some embodiments, the fibrotic disease is idiopathic pulmonary fibrosis (IPF), Dupuytren’s disease, nonalcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, cutaneous fibrosis or fibrostenotic Crohn's disease.

[0282] In some embodiments, the disease or disorder involves impairment of bone turnover. In some embodiments, the term diseases involving impairment of bone turnover refers to osteoporosis, osteopenia, hormone deficiency, hormone excess, Paget’s disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, or hypophosphatasia.

[0283] In some embodiments, the disease or disorder is associated with hypersecretion of IL-6. In some embodiments, the disease associated with hypersecretion of IL-6 is Castleman’s disease, multiple myeloma, psoriasis, Kaposi’s sarcoma, or mesangial proliferative glomerulonephritis

[0284] In some embodiments, the disease or disorder is associated with hypersecretion of TNFa, interferons, IL- 12 and / or IL-23. In some embodiments, the disease associated with hypersecretion of TNFa, interferons, IL-12 and / or IL-23 is systemic and cutaneous lupus erythematosus, lupusnephritis, dermatomyositis, Sjogren’s syndrome, psoriasis, rheumatoid arthritis, polymyalgia rheumatica, giant cell arteritis psoriatic arthritis, multiple sclerosis, trisomy 21, ulcerative colitis, or Crohn’s disease.

[0285] In some embodiments, the disease or disorder is an inflammatory disease, an autoinflammatory disease, an autoimmune disease, a proliferative disease, a fibrotic disease, transplantation rejection, a disease involving impairment of cartilage turnover, congenital cartilage malformation, a diseases involving impairment of bone turnover, a disease associated with hypersecretion of IL-6, a disease associated with hypersecretion of TNFa, interferons, IL- 12 and / or IL-23, a respiratory disease, an endocrine and / or metabolic disease, a cardiovascular disease, a dermatological disease, or an abnormal angiogenesis associated disease.

[0286] In other aspects, the present invention also provides methods for treating conditions or disorders including:Arthritis, including rheumatoid arthritis, juvenile arthritis, and psoriatic arthritis;Autoimmune or inflammatory diseases or disorders, including Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, autoimmune hepatitis, primary sclerosing cholangitis, chronic aggressive hepatitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis ulcerative colitis and membranous glomerulopathy, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, Sjogren's syndrome, Reiter's syndrome, polymyositis, dermatomyositis, type I interferonopathies including Aicardi-Goutieres syndrome and other mendelian diseases of overexpression of type I interferon systemic sclerosis, polyarteritis nodosa, multiple sclerosis, relapsing remitting multiple sclerosis, primary progressive multiple sclerosis, secondary progressive multiple sclerosis, and bullous pemphigoid, and additional autoimmune diseases, which can be O-cell (humoral) based or T-cell based, including Cogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, Type I or juvenile onset diabetes, gout, thyroiditis or bacterial sepsis; Diabetes, including Type I diabetes or complications from diabetes;Eye diseases, disorders or conditions including autoimmune diseases of the eye, keratoconjunctivitis, vernal conjunctivitis, uveitis including non-infectious uveitis associated with Behcet's disease, non-infectious uveitis, and lens-induced uveitis, keratitis, herpetickeratitis, conical keratitis, corneal epithelial dystrophy, keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis, Grave's ophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye), phlyctenule, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmitis, allergic conjunctivitis, or ocular neovascularization; Intestinal inflammations, including Crohn’s disease, ulcerative colitis, pouchitis, inflammatory bowel disease, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, gastrointestinal mucositis, oral mucositis or pouchitis;Neurodegenerative diseases including motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, or neurodegenerative disease caused by traumatic injury, strike, glutamate neurotoxicity or hypoxia; ischemic / reperfusion injury in stroke, myocardial ischemia, renal ischemia, heart attacks, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia, or platelet aggregation; Skin diseases, conditions or disorders including atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummular dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, Vogt-Koyanagi-Harada disease, Sutton nevus / nevi, post inflammatory hypopigmentation, senile leukoderma, chemical / drug-induced leukoderma, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome, hidradenitis suppurativa, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis;Allergic reactions including allergic dermatitis in mammal (including horse allergic diseases such as bite hypersensitivity), summer eczema, sweet itch in horses, heaves, inflammatory airway disease, recurrent airway obstruction, airway hyper- responsiveness, or chronic obstruction pulmonary disease;Asthma and other obstructive airways diseases, including chronic or inveterate asthma, late asthma, bronchitis, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, or dust asthma; andTransplant rejection, including pancreas islet transplant rejection, bone marrow transplant rejection, graft-versus-host disease, organ and cell transplant rejection such as bone marrow, cartilage, cornea, heart, intervertebral disc, islet, kidney, limb, liver, lung, muscle, myoblast, nerve, pancreas, skin, small intestine, or trachea, or xeno transplantation.

[0287] In some embodiments, the present invention provides a method of treating ovarian cancer in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0288] In some embodiments, the present invention provides a method of treating breast cancer in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0289] In some embodiments, the present invention provides a method of treating acute myeloid leukemia in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0290] In some embodiments, the present invention provides a method of treating multiple myeloma in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0291] In some embodiments, the present invention provides a method of treating fibrotic diseases in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0292] In some embodiments, the present invention provides a method of treating transplantation rejection diseases involving impairment of cartilage turnover in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0293] In some embodiments, the present invention provides a method of treating congenital cartilage malformation in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0294] In some embodiments, the present invention provides a method of treating diseases involving impairment of bone turnover in a patient in need thereof, wherein the method comprisesadministering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0295] In some embodiments, the present invention provides a method of treating diseases associated with hypersecretion of TNFα, interferons, IL-6, IL-12 and / or IL-23 in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0296] In some embodiments, the present invention provides a method of treating respiratory diseases in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0297] In some embodiments, the present invention provides a method of treating endocrine and / or metabolic diseases in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0298] In some embodiments, the present invention provides a method of treating cardiovascular diseases, including pulmonary arterial hypertension or complications from pulmonary arterial hypertension in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0299] In some embodiments, the present invention provides a method of treating dermatological diseases in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0300] In some embodiments, the present invention provides a method of treating abnormal angiogenesis associated diseases in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0301] In some embodiments, the SIK2-mediated disorder is inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis, diabetes, a skin pigmentation disease, osteoporosis, osteoarthritis, lupus (systemic lupus erythematosus), a musculoskeletal disease, or rheumatoid arthritis.

[0302] In some embodiments, the SIK2-mediated disorder is Bone-mineral disorders, including chronic kidney disease. In some embodiments, the SIK2-mediated disorder is a mineral bone disorder. In some embodiments, the SIK2-mediated disorder is a mineral loss disorder, such as Malignancy-related and oncology drug-related bone loss, and osteoporosis (post-menopausal, glucocorticoid-induced, hypogonadal).

[0303] In some embodiments, the SIK2-mediated disorder is Ankylosing Spondylitis, Psoriatic Arthritis, Crohn's Disease (Active and Maintenance), Plaque Psoriasis, Juvenile Idiopathic Arthritis, Ulcerative Colitis, Hidradenitis Suppurativa, Uveitis, and non-radiographic axial spondyloarthritis.

[0304] In some embodiments, the present invention provides a method of treating inflammatory bowel disease in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0305] In some embodiments, the present invention provides a method of treating diabetes in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0306] In some embodiments, the present invention provides a method of treating a skin pigmentation disease in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0307] In some embodiments, the present invention provides a method of treating osteoporosis in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0308] In some embodiments, the present invention provides a method of treating osteoarthritis in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0309] In some embodiments, the present invention provides a method of treating a musculoskeletal disease in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0310] In some embodiments, the present invention provides a method of treating rheumatoid arthritis in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.

[0311] It is understood that appropriate doses of the active compound depends upon a number of factors within the knowledge of the ordinarily skilled physician or veterinarian. The dose(s) of the active compound will vary, for example, depending upon the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, and any drug combination.

[0312] It will also be appreciated that the effective dosage of a compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof used for treatment may increase or decrease over the course of a particular treatment. Changes in dosage may result and become apparent from the results of diagnostic assays.

[0313] In some embodiments, the SIK2 inhibitor is administered to the subject at a dose of between about 0.001 μg / kg and about 1000 mg / kg, including but not limited to about 0.001 μg / kg, 0.01 μg / kg, 0.05 μg / kg, 0.1 μg / kg, 0.5 μg / kg, 1 μg / kg, 10 μg / kg, 25 μg / kg, 50 μg / kg, 100 μg / kg, 250 μg / kg, 500 μg / kg, 1 mg / kg, 5 mg / kg, 10 mg / kg, 25 mg / kg, 50 mg / kg, 100 mg / kg, and 200 mg / kg.

[0314] In some embodiments, the SIK2 inhibitor is administered to the subject at a dose of between about 0.1 mg and about 10 g, including but not limited to about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, 500 mg, 750 mg, 1 g, 2 g, 5 g, and 10 g.

[0315] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0316] In some embodiments, the compounds of the invention are useful in preventing or reducing the risk of developing any of the diseases referred to herein; e.g., preventing or reducing the riskof developing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.

[0317] Additionally, provided are SIK2 inhibitors for use as therapeutic active substances. A SIK2 inhibitor for use in treating or preventing a SIK2-mediated disorder provided herein. Further provided is the use of a SIK2 inhibitor in the manufacture of a medicament for treating or preventing a SIK2-mediated disorder provided herein.

[0318] The term "administration" or "administering" includes routes of introducing the compound(s) to a subject to perform their intended function. Examples of routes of administration which can be used include injection (subcutaneous, intravenous, parenterally, intraperitoneally, intrathecal), topical, oral, inhalation, rectal and transdermal.

[0319] The term "effective amount" includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result. An effective amount of compound may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response.

[0320] The phrases "systemic administration," "administered systemically", "peripheral administration" and "administered peripherally" as used herein mean the administration of a compound(s), drug or other material, such that it enters the patient's system and, thus, is subject to metabolism and other like processes.

[0321] The phrase "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.

[0322] The term "subject" refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human.5. Combination Therapies

[0323] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents, which are normally administered to treat that condition, may be administered in combination with compounds and compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.” In certain embodiments, a provided combination, or composition thereof, is administered in combination with another therapeutic agent.

[0324] Those additional agents may be administered separately from a provided combination therapy, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another.

[0325] As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a combination of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.

[0326] The amount of additional therapeutic agent present in the compositions of this invention will be no more than 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 presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0327] In one embodiment, the present invention provides a composition comprising a compound of formula I and one or more additional therapeutic agents. The therapeutic agent may be administered together with a compound of formula I or may be administered prior to or following administration of a compound of formula I. In certain embodiments, a compound of formula I may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, a compound of formula I may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours,10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours following the therapeutic agent.

[0328] A compound of the current invention may also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation. In certain embodiments, a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.

[0329] A compound of the current invention can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.General Synthesis Description

[0330] Examples of the invention of general formula O and P can be prepared as described in scheme 1. For that purpose, methyl pyridine derivative A is converted to benzyl bromide B under radical bromination conditions. Substitution of benzylic bromide in compound B with a cyanide leads to nitrile C. Compound C upon treatment with an N-transfer reagent such as O-(mesitylsulfonyl)hydroxylamine (generated in situ from tert-butyl ((mesitylsulfonyl)oxyjcarbamate upon treatment with trifluoroacetic acid) is converted to 1-aminopyridinium derivative D. Compound D undergoes cyclization in the presence of base such as potassium carbonate in an organic solvent such as methanol to form heterocycle E. The amino group in E is protected by means of heating with phthalic anhydride in a solvent such as toluene to give phthalimide derivative F. Compound F is reacted with a boronic acid of general formula G (R1= C1-C3-alkyl, optionally fluorinated) under Suzuki-Miyaura cross-coupling conditions to yield cross-coupling product H. Preparation of boronic acids of general formular G is described in the experimental section of the description of the present invention. Treatment of compound H with a Lewis acid such as aluminum (III) chloride in aprotic organic solvent such as 1,2-dichloroethane leads to intermediate...

Claims

1. CLAIMS1. A compound of formula I:1or a pharmaceutically acceptable salt thereof, wherein:X is N orC;Y is N or C, where when one of X and Y is N and the other of X and Y is C;Each = is a single or double bond;Li is selected from a bond, -O-, -S-, -S(O)2-, -NR1-, -C(O)-, -C(O)NR1-, -NR'C(O)-, - NR1C(O)NR1-, and -[C(R1a)(R1b)]1-2-;L2 is selected from a bond, a substituted or unsubstituted alkenylene, -O-, -S-, -S(O)2-, -N= S(O)(CH3)-, -S(O)(CH3)=N-, -S(O)2NR1-, -NR1S(O)2-, -NR1-, -C(O)-, -C(O)NR1-, - NR^tO)-, -NR1C(O)NR1-, an optionally substituted C3-Ce cycloalkyl, an optionally substituted C3-C6 heterocycloalkyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and-[C(R2a)(R2b)]1-2-;L3is selected from a bond, a substituted or unsubstituted alkenylene, -O-, -S-, -S(O)2-, -N= S(O)(CH3)-, -S(O)(CH3)=N-, -S(O)2NR1-, -NR1S(O)2-, -NR1-, -C(O)-, -C(O)NR1-, - NR^ O)-, -NR1C(O)NR1-, an optionally substituted C3-Ce cycloalkyl, an optionally substituted C3-Ce heterocycloalkyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and-[C(R3a)(R3b)]i-2-;L4 is selected from a bond, a substituted or unsubstituted alkenylene, -O-, -S-, -S(O)2-, -N= S(O)(CH3)-, -S(O)(CH3)=N-, -S(O)2NR1-, -NR1S(O)2-, -NR1-, -C(O)-, -C(O)NR1-, -NR1C(O)-, -NR1C(O)NR1-, an optionally substituted C3-Ce cycloalkyl, an optionallysubstituted C3-C6 heterocycloalkyl (having 1 -4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), an optionally substituted 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and -[C(R4a)(R4b)]i-2-;L5 is selected from a bond, -O-, -S-, -S(O)2-, -NR1-, -C(O)-, -C(O)NRJ-, -NR1C(O)-, -NR1C(O)NR1-, and -[C(R5a)(R5b)]1-2-;Each R1is independently selected from the group consisting of hydrogen, C1-3 haloalkyl, C1-3 hydroxyalkyl, C0-3 alkyl-C3-Ce cycloalkyl, C0-3alkyl-C1-C6heterocycloalkyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and C1-3 alkyl; wherein C0-3alkyl-C3-C6cycloalkyl, C0-3alkyl-C3-C6heterocycloalkyl and C1-3 alkyl are substituted with y instances of RB;each RBis independently halogen, C1-3 alkyl, C1-3 hydroxyalkyl, -CN, oxo, -OR, or -NR2; each y is independently 0, 1, 2, or 3;Rla, Rlb, R2a, R2b, R3a, R3b, R4a, R4b, R5a, and R5bare independently selected from the group consisting of hydrogen, halogen, hydroxyl, N(R1)2, C1-3 alkyl, -CN, C1-3 alkoxy, C0-3 alkyl- C3-C6 cycloalkyl, C0-3alkyl-C1-C6heterocycloalkyl, and C1-3 hydroxyalkyl, and C1-3 haloalkyl, wherein C0-3 alkyl-C3-C6 cycloalkyl, C0-3 alkyl-C3-C6 heterocycloalkyl and C1-3 alkyl are substituted with y instances of RB; orRlaand Rlb, R2aand R2b, R3aand R3b, R4aand R4b, or R5aand R5b, and the carbon atom to which they are attached may combine to form:a) a 3-7 membered saturated or partially unsaturated bivalent monocyclic carbocyclylene or 4-7 membered saturated or partially unsaturated bivalent heterocyclylene ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 nitrogen atoms in addition to the 1-4 heteroatoms) - substituted with y instances of RB, orb) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene or heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) - substituted with y instances of RB, orRlaand R2a, Rlaand R3a, R2aand R3a, R2aand R4a, R3aand R4a, R3aand R5a, or R4aand R5a, and the atoms to which they are connected may combine to form:a) a 3-7 membered saturated or partially unsaturated bivalent monocyclic carbocyclylene or a 4-7 membered saturated or partially unsaturated bivalent heterocyclylene ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 0 or 1 nitrogen atoms in addition to the 1-4 heteroatoms) - substituted with y instances of RB, orb) a 4-12 membered saturated or partially unsaturated bivalent bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclylene or heterocyclylene (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur) - substituted with y instances of RB;Xi and X2 are each selected from N and CR2provided when Y is N, Xi is CR2;each R2is independently selected from hydrogen, OH, C1-3 alkyl, C1-3 alkoxy, and halogen; X3 is selected from O, S, N, NR7, and CR2, provided when X3 is selected from O, S, and NR7, X and Y areC;R7is hydrogen or C1-3 alkyl;Ring C is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7- 12 membered saturated or partially unsaturated bicyclic heterocyclyl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each R1Ais independently halogen, -CN, oxo, -OR, -SR, -NR2, -SO2R, -SO2NR2, -S(O)R, - S(O)NR2, -C(O)R, -CO2R, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)CO2R, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)R, -N(R)C(NR)NR2, -N(R)NR2, -N(R)SO2NR2, -N(R)SO2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, - P(O)(OR)2, -P(O)R2, CI-C6haloalkyl, C1-3 hydroxyalkyl, C3-C6 halocycloalkyl, Ci-Ce haloalkoxy, or an optionally substituted group selected from Ci-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;a is 0, 1, 2, or 3;R3is -C(O)-Le, -S(O)2-L6, an optionally substituted C1-6 aliphatic, an optionally substituted C1-6aliphatic substituted with an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from(R6B)bnitrogen, oxygen, and sulfur, or (R6A)C;Le is selected from the group consisting ofRing D is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 7-14 membered saturated or partially unsaturated tricyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Each R8is independently selected from hydrogen, halogen, hydroxyl, -CN, C1-4 alkoxy, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic, C1-C6 haloalkyl, and C1-4 alkyl; or two R8groups and the atom to which they are attached can form oxo, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring or a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R9is selected from hydrogen, Ci-Ce alkyl, Ci-Cehaloalkyl, C1-3 hydroxyalkyl, Ci-Ce alkoxy, Ci- Ce haloalkoxy, and an optionally substituted C 1-6 aliphatic; orR9is a cyclic group or an optionally substituted C1-6 aliphatic substituted with a cyclic group, wherein the cyclic group is selected from:• phenyl;• a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring;• a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• an 8-10 membered bicyclic hetero aromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• a 5- 12 membered saturated or partially unsaturated bicyclic carbocyclic ring that is optionally bridged or spirocyclic; and• a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the cyclic group is substituted with y instances of RA;each R6Ais independently a C1-6 aliphatic-cyclic or cyclic group, wherein the cyclic group is selected from:• a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• an 8-10 membered bicyclic hetero aromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring that is optionally bridged or spirocyclic; and• a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein R6Ais substituted with y instances of RA;each R6Bis independently halogen, -CN, oxo, -OR, -SR, -NR2, -SO2R, -SO2NR2, -S(O)R, - S(O)NR2, -C(O)R, -CO2R, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, - N(R)CO2R, -N(R)C(O)R, N(R)C(O)NR2, N(R)C(NR)R, N(R)C(NR)NR2, N(R)NR2, -N(R)SO2NR2, -N(R)SO2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, - P(O)(OR)2, -P(O)R2, or an optionally substituted group selected from Ci-6 aliphatic; a 3- 7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;b is 0, 1, 2, or 3;c is 0, 1, 2, or 3;each RAis independently selected from deuterium, a C1-6 aliphatic group substituted with 0, 1, 2, or 3 groups independently selected from halogen, deuterium, -CN, -NR2, and -OR; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, -CN, -NR2, and -OR; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, -CN, -NR2, and - OR; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring substituted with 0, 1, 2, or 3 groups independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, -CN, -NR2, and -OR; a 4- 12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl and heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0, 1, 2, or3 groups independently selected C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, C1-3 hydroxyalkyl, halogen,-CN, -OR, and -NR2; halogen; -CN; -NO2; -OR; SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; -C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)NR2; -N(R)C(NR)NR2; -S(NR)(O)R; -N(R)S(O)2NR2; and -N(R)S(O)2R; ortwo RAon the same atom together form oxo or a cyclic group selected from:• 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; and • a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the cyclic group formed by two RAon the same atom is substituted with 0, 1, 2, or 3 groups independently selected from a Ci-6 aliphatic group substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; halogen; -CN; -NO2; -OR;SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; - C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; - N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; and -N(R)S(O)2R; or two RAon adjacent atoms form a cyclic group selected from:• 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; • a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• phenyl; and• a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the cyclic group formed by two RAon adjacent atoms is substituted with 0, 1, 2, or 3 groups independently selected from a Ci-6 aliphatic group substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NR2, and -OR; halogen; -CN; -NO2; -OR;SR; -NR2; -S(O)2R; -S(O)2NR2; -S(O)R; -S(O)NR2; -C(O)R; -C(O)OR; - C(O)NR2; -C(O)N(R)OR; -OC(O)R; -OC(O)NR2; -N(R)C(O)OR; -N(R)C(O)R; - N(R)C(O)NR2; -N(R)C(NR)NR2; -N(R)S(O)2NR2; and -N(R)S(O)2R;each R is independently hydrogen, -C(O)N(CH3)2, -C(O)2CH3, -C(O)2C(CH3)3, -C(O)2CH(CH3)2, -S(O)2CH33, an optionally substituted Ci-6 aliphatic group, an optionally substituted cyclic group, or an optionally substituted Ci-6 alkyl-cyclic group, wherein the cyclic group is selected from:• an optionally substituted phenyl;• an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring;• an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• an optionally substituted 5-8 membered saturated or partially unsaturated bridged bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;• an optionally substituted 6-10 membered saturated or partially unsaturated spirocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and• an optionally substituted 6-11 membered saturated or partially unsaturated bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and / ortwo R groups on the same atom are taken together with the same atom to form a cyclic group selected from:• an optionally substituted 4-7 membered saturated or partially unsaturated carbocyclyl;• an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and• an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur,wherein the optionally substituted R moiety is substituted with 0, 1, 2, 3, or 4 RSub; each RSubis independently selected from Ci-6 aliphatic group substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -N(RN)2, and -O RN; halogen; -CN; -NO2; -ORN; -SRN; -N(RN)2; -S(O)2RN; -S(O)2N(RN)2; -S(O)RN; -S(O)N(RN)2;-C(O)RN; -C(O)ORN; -C(O)N(RN)2; -C(O)N(RN)ORN; -OC(O)RN; -OC(O)N(RN)2;-N(RN)C(O)ORN; -N(RN)C(O)RN; -N(RN)C(O)N(RN)2; -N(RN)C(NRN)N(RN)2;-N(RN)S(O)2N(RN)2; and -N(RN)S(O)2RN; and each RNis independently selected from H and Ci-3 alkyl.

2. The compound of claim 1, wherein said compound is of any one of the following formulae I-a, I-b, or I-c:or a pharmaceutically acceptable salt thereof, wherein:Ring C is a 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, andX1and X2are independently selected from N, CF, CCl, CCH3, and CH, provided that only one of X1and X2may be N.

3. The compound of claim 1 or claim 2, wherein Ring C is a 5-membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

4. The compound of claim 1 or claim 2, wherein Ring C is5. The compound of any one of claims 1-4, wherein said compound is a compound of formulae II-a, II-b, II-c, II-d, or II-e:Il-eor a pharmaceutically acceptable salt thereof, wherein:X1and X2are independently selected from N, CF, CCl, and CH.

6. The compound of any one of claims 1-4, wherein said compound is a compound of formulae III-a, III-b, III-c, III-d, or III-e:III-eor a pharmaceutically acceptable salt thereof, wherein:X1and X2are independently selected from N, CF, CCl, and CH.

7. The compound of any one of claims 1-4, wherein said compound is a compound of formulae IV-a, IV-b, IV-c, IV-d, or VI-e:or a pharmaceutically acceptable salt thereof, wherein:X1, and X2are independently selected from CH, N, CF, CCl, CCH3, andL6is selected from the group consisting of8. The compound of claims 1-7, wherein L1is -CH2- or -O- and L5is -CH2- or -O-.

9. The compound of any one of claims 1-4 or 8, wherein said compound of formula I is a compound of formulae V-a, V-b, V-c, V-d, or V-e:V-eor a pharmaceutically acceptable salt thereof, wherein:X1and X2are independently selected from CH, N, CF, CCl, and CCH3.

11. The compound of any one of the claims 1-10, wherein the compound is selected from those depicted in Table 1, or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

13. The compound of any one of claims 1-11, or the pharmaceutical composition of claim 12, for use as a medicament.

14. A method of inhibiting SIK2 in a biological sample, comprising contacting the sample with the compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 12.

15. A method of treating an SIK2-mediated disorder, disease, or condition in a patient, comprising administering to said patient the compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 12.

16. The method of claim 15, wherein the SIK2-mediated disorder is selected from inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of TNFα, interferons, IL-6, IL-12 and / or IL-23, respiratory diseases, endocrine and / or metabolic diseases, cardiovascular diseases, dermatological diseases, and abnormal angiogenesis associated diseases.

17. The method of claim 15, wherein the SIK2-mediated disorder is a cancer selected from ovarian cancer, breast cancer, acute myeloid leukemia, and multiple myeloma.

18. The method of claim 15, wherein the SIK2-mediated disorder is inflammatory bowel disease, diabetes, a skin pigmentation disease, osteoporosis, osteoarthritis, a musculoskeletal disease, or rheumatoid arthritis.

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