CAMKK2 Modulators as Ligand-Directed Degraders

Abstract

TIFF2024537197000069.tif4194I Provided herein are compounds of formula I and compositions thereof for modulating CAMKK2. In some embodiments, the compounds and compositions are provided for treating cancer and / or obesity.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 253,721, filed October 8, 2021, which is incorporated by reference in its entirety herein for all purposes.

[0002] The present disclosure relates generally to compounds, compositions, and methods for their preparation and use for the treatment of cancer. [Background technology]

[0003] Tumor-associated myeloid cells play a central role in regulating processes that control tumor growth and metastasis, and their accumulation in cancer tumors has been identified as an important negative prognostic factor. Calcium / calmodulin-dependent protein kinase kinase 2 (CAMKK2) has been shown to be highly expressed in intratumoral myeloid cells in a mouse model of breast cancer, and its inhibition in myeloid cells inhibits the effector CD8 + Inhibiting tumor growth by increasing the intratumoral accumulation of T cells and immune-stimulatory myeloid cell subsets (Racioppi et al., Nat Commun. 2019 Jun 4;10(1);2450). Furthermore, decreased CAMKK2 activity suppresses tumor growth by increasing the intratumoral accumulation of T cells and immune-stimulatory myeloid cell subsets (Racioppi et al., Nat Commun. 2019 Jun 4;10(1);2450). Furthermore, decreased CAMKK2 activity suppresses the accumulation of macrophages expressing high levels of major histocompatibility class II IA (MHC II IA) and CD8 +It has been shown that CAMKK2 expression is associated with the accumulation of T cells (WO 2018 / 027223). Treatment with a CAMKK2 inhibitor inhibits tumor growth and promotes reprogramming of the tumor microenvironment (WO 2018 / 027223). In human breast cancer biopsies, CAMKK2 expression levels correlate with tumor grade, and in aggressive tumors, both tumor cells and tumor-associated macrophages express high levels of this enzyme (WO 2018 / 027223). These findings suggest that CAMKK2 is a macrophage-specific checkpoint and reveal that CAMKK2 inhibition may be an innovative therapeutic strategy in cancer treatment via reprogramming of the tumor microenvironment.

[0004] In addition to cancer therapy, CAMKK2 inhibition promotes weight loss, which could have major medical and societal benefits. CAMKK2 null mice were able to consistently abstain from high-fat diets, lose weight, lose adiposity, and have improved glucose sensitivity relative to wild-type littermates (Anderson et al., Cell Metab. 2008, 7, 377). From a mechanistic perspective, CAMKK2 null mice are highly resistant to ghrelin-induced feeding and, similar to neuropeptide Y (NPY)-deficient mice, eat less food when re-fed after fasting compared to wild-type individuals. These recent observations are supported by pharmacological inhibition of CAMKK2 using STO-609 delivered intracerebroventricularly (Anderson et al., Cell Metab. 2008, 7, 377) or 2,4-diaryl 7-azaindoles delivered orally (Price et al., Bioorg. Med. Chem. Lett. 2018 Jun 1;28(10):1958-1963). CAMKK2 is therefore of interest as a therapeutic target for the treatment of cancer and obesity.

[0005] Protein degradation is a highly regulated and essential process that maintains cellular homeostasis. The selective identification and elimination of damaged, misfolded, or excess proteins is achieved through the ubiquitin / proteasome pathway (UPP), which is central to the regulation of almost all cellular processes. Protein ubiquitination is achieved by E3 ubiquitin ligases, which bind to proteins and add ubiquitin molecules to them, thus marking them for proteasomal degradation.

[0006] The therapeutic use of UPP has gained great interest (Zhou et al., Mol. Cell 2000, 6, 751-756). One promising treatment is the use of proteolytic chimeric molecules, commonly referred to as PROTACs, to induce the elimination of unwanted proteins by proteolysis (Scheepsta et al., Comp. Struct. Biotech. J. 2019, 17, 160-176). PROTACS are ligand-directed degraders that bring together E3 ligases and the target protein to be degraded. These bivalent molecules usually consist of a small molecule bound to the target protein and an E3 ligase ligand joined via a linker site. PROTACs position the E3 ligase at the appropriate distance and orientation to the target protein, where the latter is ubiquitinated. The ubiquitinated target protein is then recognized by the proteasome, where it is degraded.

[0007] Thus, in one aspect, provided herein are compounds that target CAMKK2 for degradation. Summary of the Invention

[0008] In some embodiments, compounds that degrade CAMKK2 and compositions comprising them are described herein. In various embodiments, the compounds and compositions thereof may be used to treat cancer and / or obesity.

[0009] The present embodiments can be more fully understood by reference to the detailed description and examples given by way of illustration of non-limiting embodiments.

[0010] Embodiment 1 is a compound of formula I [ka] I or a pharma- ceutically acceptable salt thereof. [In the formula, W is N or CX1; R1 is O or optionally substituted heteroarylene; R2 is optionally substituted aryl; X1, X2, and X3 are each independently hydrogen, halogen, or -CN; n is between 2 and 10.

[0011] Embodiment 2 is a compound of embodiment 1, or a pharma- ceutically acceptable salt thereof, wherein R1 is O.

[0012] Embodiment 3 is a compound of embodiment 1, or a pharma- ceutically acceptable salt thereof, wherein R1 is an optionally substituted heteroarylene.

[0013] Embodiment 4 is a compound of embodiment 3, or a pharma- ceutically acceptable salt thereof, Wherein R1 is pyrazolylene optionally substituted With methyl.

[0014] Embodiment 5 is a compound according to any one of embodiments 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein R2 is aryl, optionally substituted with at least one substituent selected from alkyl, carbonyl, carbocyclyl, heterocyclyl, and heteroaryl.

[0015] Embodiment 6 is a compound of embodiment 5, wherein R2 is aryl optionally substituted with C1-C3 alkyl optionally substituted with halogen or C3-C4 carbocyclyl, or a pharma- ceutically acceptable salt thereof.

[0016] Embodiment 7 is a compound of embodiment 5, or a pharma- ceutically acceptable salt thereof, wherein R2 is aryl optionally substituted with -CO2H or -C(O)NH2.

[0017] Embodiment 8 is a compound of embodiment 5, wherein R2 is aryl optionally substituted with C3-C5 carbocyclyl optionally substituted with halogen, or a pharma- ceutically acceptable salt thereof.

[0018] Embodiment 9 is a compound according to embodiment 5, wherein aryl is optionally substituted with a 6-membered heterocyclyl containing a nitrogen atom, or a pharma- ceutically acceptable salt thereof.

[0019] Embodiment 10 is a compound of embodiment 5, or a pharma- ceutically acceptable salt thereof, wherein R2 is aryl optionally substituted with tetrazolyl.

[0020] Embodiment 11 is a compound according to any one of embodiments 1 to 10, or a pharma- ceutically acceptable salt thereof, wherein W is N.

[0021] Embodiment 12 is a compound according to any one of embodiments 1 to 10, or a pharma- ceutically acceptable salt thereof, wherein W is CX1.

[0022] Embodiment 13 is a compound of embodiment 12, or a pharma- ceutically acceptable salt thereof, wherein X1 is hydrogen or halogen.

[0023] Embodiment 14 is a compound according to any one of embodiments 1 to 13, or a pharma- ceutically acceptable salt thereof, wherein X2 and X3 are each independently hydrogen or halogen.

[0024] Embodiment 15 is a compound according to any one of embodiments 1 to 14, or a pharma- ceutically acceptable salt thereof, wherein n is any one of 4 to 9.

[0025] Embodiment 16 is a compound of claim 1, or a pharma- ceutically acceptable salt thereof, having the formula Ia. [ka] Ia

[0026] Embodiment 17 is a compound of embodiment 16, or a pharma- ceutically acceptable salt thereof, wherein n is 4 to 9.

[0027] Embodiment 18 is a compound of embodiment 17, or a pharma- ceutically acceptable salt thereof, wherein n is 4.

[0028] Embodiment 19 is a compound of embodiment 17, or a pharma- ceutically acceptable salt thereof, wherein n is 5.

[0029] Embodiment 20 is a compound of embodiment 17, or a pharma- ceutically acceptable salt thereof, wherein n is 6.

[0030] Embodiment 21 is a compound of embodiment 17, or a pharma- ceutically acceptable salt thereof, wherein n is 7.

[0031] Embodiment 22 is a compound of embodiment 17, or a pharma- ceutically acceptable salt thereof, wherein n is 8.

[0032] Embodiment 23 is a compound of embodiment 17, or a pharma- ceutically acceptable salt thereof, wherein n is 9.

[0033] Embodiment 24 is a compound selected from the compounds set forth in Table 1, or a pharma- ceutically acceptable salt thereof.

[0034] Embodiment 25 is a pharmaceutical composition comprising a compound according to any one of embodiments 1 to 24, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0035] Embodiment 26 is a method for controlling gene transcription in a cell, comprising modulating calcium / calmodulin-dependent protein kinase kinase 2 (CAMKK2) activity by exposing CAMKK2 to a compound according to any one of embodiments 1 to 24, or a pharma- ceutically acceptable salt thereof, or to a pharmaceutical composition according to embodiment 25.

[0036] Embodiment 27 is a method for modulating calcium / calmodulin-dependent protein kinase kinase 2 (CAMKK2), comprising contacting CAMKK2 with an effective amount of a compound according to any one of embodiments 1 to 24, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 25.

[0037] Embodiment 28 is a method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of embodiments 1 to 24, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 25.

[0038] Embodiment 29 is the method of embodiment 28, wherein the cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), neuroblastoma, small round blue cell tumor, glioblastoma, glioma, prostate cancer, breast cancer, bladder cancer, lung cancer, or melanoma. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0039] (Detailed Description) (definition) As used herein, the terms "comprising" and "including" can be used interchangeably. The terms "comprising" and "including" are to be interpreted to specify that the stated features or components are present exactly as stated, but do not exclude the presence or addition of one or more features, components, or groups thereof. In addition, the terms "comprising" and "including" include examples encompassed by the term "consisting of." Thus, the term "consisting of" can be used in place of the terms "comprising" and "including" to provide more specific embodiments of the invention.

[0040] The term "consisting of" means that the subject matter has at least 90%, 95%, 97%, 98%, or 99% of the recited features or components that make it up. In other embodiments, the term "consisting of" excludes from the ensuing description any other features or components, except those that are not essential to the technical effect to be achieved.

[0041] As used herein, the term "or" is to be interpreted as an inclusive "or" meaning any one or any combination. Thus, "A, B, or C" means any of the following: "A; B; C; A and B; A and C; B and C; A, B, and C."

[0042] Unless otherwise indicated herein, any concentration range, percentage range, proportion range, or integer range should be understood to include any integer value within the stated range and, where appropriate, fractions thereof (e.g., tenths and hundredths of an integer value). Also, unless otherwise indicated, any numerical range relating to any physical characteristic described herein, such as a polymer subunit, size, or thickness, should be understood to include any integer value within the stated range. As used herein, unless otherwise indicated, the terms "about" and "approximately" mean ±20%, ±10%, ±5%, or ±1% of the indicated range, value, or structure.

[0043] "Amino" refers to the group -NH2.

[0044] "Cyano" refers to the radical -CN.

[0045] "Nitro" refers to the -NO2 group.

[0046] "Oxa" refers to the group --O--.

[0047] "Oxo" refers to the group ═O.

[0048] "Thioxo" refers to the group ═S.

[0049] "Imino" refers to the group ═NH.

[0050] "Oximo" refers to the group =N-OH.

[0051] "Hydrazino" refers to the group =N-NH2.

[0052] "Alkyl" refers to a straight or branched chain hydrocarbon group containing no unsaturation, having from 1 to 15 carbon atoms, and consisting solely of carbon and hydrogen atoms (e.g., C1-C 15 In some embodiments, alkyl contains 1 to 13 carbon atoms (e.g., C1 to C6). 13In some embodiments, the alkyl comprises 1-8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl comprises 1-5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl comprises 1-4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl comprises 1-3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl comprises 1-2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl comprises 1 carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl comprises 5-15 carbon atoms (e.g., C5-C6 alkyl). 15 In other embodiments, the alkyl group comprises 5-8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group comprises 2-5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group comprises 3-5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group comprises 5-8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group comprises 2-5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group comprises 3-5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). The alkyl group is attached to the remainder of the molecule by a single bond. Unless stated otherwise in the specification, the alkyl group may be optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR. a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a(where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), and S(O) t N(R a )2, where t is 1 or 2, where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0053] "Alkoxy" refers to a radical of the formula --O-alkyl, where alkyl is an alkyl chain as defined above, attached via an oxygen atom.

[0054] "Alkenyl" refers to a straight or branched chain hydrocarbon group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, having 2 to 12 carbon atoms. In some embodiments, an alkenyl contains 2 to 8 carbon atoms. In other embodiments, an alkenyl contains 2 to 4 carbon atoms. An alkenyl is attached to the remainder of the molecule by a single bond and is, for example, ethenyl (i.e., vinyl), 1-propenyl (i.e., allyl), 1-butenyl, 1-pentenyl, penta-1,4-dienyl, and the like. Unless stated otherwise in the specification, an alkenyl group may be optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, -O- ... a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), and S(O) t N(R a )2, where t is 1 or 2, where R aare each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0055] "Alkynyl" refers to a straight or branched chain hydrocarbon group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having 2 to 12 carbon atoms. In some embodiments, alkynyl contains 2 to 8 carbon atoms. In other embodiments, alkynyl contains 2 to 4 carbon atoms. An alkynyl is attached to the remainder of the molecule with a single bond and is, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise in the specification, alkynyl groups may be optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, -O- ... a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(Ra )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), and S(O) t N(R a )2, where t is 1 or 2, where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0056] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon, containing no unsaturated bonds, having 1-12 carbon atoms, consisting only of carbon and hydrogen, and linking the remainder of the molecule to a group, such as, for example, methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is attached to the rest of the molecule by a single bond and to the group by a single bond. The alkylene chain is attached to the rest of the molecule and to the group through a carbon atom in the alkylene chain or through any two carbon atoms in the chain. In some embodiments, the alkylene contains 1-8 carbon atoms (e.g., C1-C8 alkylene). In other embodiments, the alkylene contains 1-5 carbon atoms (e.g., C1-C5 alkylene). In other embodiments, the alkylene contains 1-4 carbon atoms (e.g., C1-C4 alkylene). In other embodiments, the alkylene comprises 1-3 carbon atoms (e.g., C1-C3 alkylene). In other embodiments, the alkylene comprises 1-2 carbon atoms (e.g., C1-C2 alkylene). In other embodiments, the alkylene comprises 1 carbon atom (e.g., C1 alkylene). In other embodiments, the alkylene comprises 5-8 carbon atoms (e.g., C5-C8 alkylene). In other embodiments, the alkylene comprises 2-5 carbon atoms (e.g., C2-C5 alkylene). In other embodiments, the alkylene comprises 3-5 carbon atoms (e.g., C3-C5 alkylene). Unless stated otherwise in the specification, an alkylene chain may be optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR. a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t Ra (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), and S(O) t N(R a )2, where t is 1 or 2, where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0057] "Aryl" refers to a group derived from a monocyclic or polycyclic aromatic hydrocarbon ring system by removing one hydrogen atom from a ring carbon atom. The monocyclic or polycyclic aromatic hydrocarbon ring system contains only hydrogen and 5-18 carbon atoms, and at least one ring in the ring system is fully unsaturated, i.e., it contains a cyclically delocalized (4n+2) pi-electron system that satisfies Hückel's rule. Ring systems from which aryl groups are derived include, but are not limited to, benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless stated otherwise in the specification, the term "aryl" or its prefix "ar" (e.g., in aralkyl) is intended to include aryl groups which are optionally substituted with one or more substituents independently selected from the following substituents: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -Rb -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and R b -S(O) t N(R a )2, where t is 1 or 2, where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); R b are each independently a direct bond or a straight or branched chain alkylene or alkenylene; R c is a straight or branched chain alkylene or alkenylene, further wherein, unless otherwise specified, each of the above substituents is unsubstituted.

[0058] "Aralkyl" is a group of the formula -R c -aryl (where R c refers to an alkylene chain as defined above (e.g., methylene, ethylene, etc.). The alkylene chain portion of the aralkyl group may be optionally substituted as described above for alkylene chains. The aryl portion of the aralkyl group may be optionally substituted as described above for aryl groups.

[0059] "Aralkenyl" is a group of the formula -R d -aryl (where R d refers to a radical represented by an alkenylene chain as defined above. The aryl part of the aralkenyl group may be optionally substituted as defined above for an aryl group. The alkenylene chain part of the aralkenyl group may be optionally substituted as defined above for an alkenylene group.

[0060] "Aralkynyl" refers to a group of the formula -R e -aryl (where R e is an alkynylene chain as defined above. The aryl part of the aralkynyl group may be optionally substituted as defined above for an aryl group. The alkynylene chain part of the aralkynyl group may be optionally substituted as defined above for an alkynylene chain.

[0061] "Aralkoxy" is a group of the formula -OR c -aryl (where R c refers to an alkylene chain, as defined above (e.g., methylene, ethylene, etc.), attached through an oxygen atom. The alkylene chain portion of the aralkyl group may be optionally substituted as described above for alkylene chains. The aryl portion of the aralkyl group may be optionally substituted as described above for aryl groups.

[0062] "Carbocyclyl" refers to a stable monocyclic or polycyclic non-aromatic hydrocarbon group, consisting solely of carbon and hydrogen atoms, including fused or bridged ring systems, having from 3 to 15 carbon atoms. In some embodiments, a carbocyclyl contains from 3 to 10 carbon atoms. In other embodiments, a carbocyclyl contains from 5 to 7 carbon atoms. A carbocyclyl is attached to the remainder of the molecule by a single bond. A carbocyclyl may be saturated (i.e., containing only single C-C bonds) or unsaturated (i.e., containing one or more double or triple bonds). Fully saturated carbocyclyl groups are also referred to as "carbocyclyls". Examples of monocyclic carbocyclyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclyls may also be referred to as "cycloalkenyls". Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7 dimethylbicyclo[2.2.1]heptanyl, and the like. Unless stated otherwise in the specification, the term "carbocyclyl" is intended to include carbocyclyl groups which are optionally substituted with one or more substituents independently selected from the following substituents: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)ORa , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), and S(O) t N(R a )2, where t is 1 or 2, where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); R b are each independently a direct bond or a straight or branched chain alkylene or alkenylene; R c is a straight or branched chain alkylene or alkenylene, further wherein, unless otherwise specified, each of the above substituents is unsubstituted.

[0063] A "carbocyclylalkyl" is a group of the formula -R c -Carbocyclyl (where R c is an alkylene chain as defined above. The alkylene chain and carbocyclyl group may be optionally substituted as defined above.

[0064] "Carbocyclylalkoxy" has the formula -OR c -Carbocyclyl (where R c is an alkylene chain as defined above), which may be optionally substituted as defined above.

[0065] "Carbocyclylalkynyl" has the formula -R c -Carbocyclyl (where R c is an alkynylene chain as defined above. The carbocyclyl part of the carbocyclylalkynyl group may be optionally substituted as defined above for a carbocyclyl group. In some embodiments the carbocyclyl group is a carbocyclyl group. The alkynylene chain part of the carbocyclylalkynyl group may be optionally substituted as defined above for an alkynylene chain.

[0066] "Carbonyl" has the formula -C(O)R 10 R 20 where R 10 and R 20 each independently represents -OH, halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -R a , -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)ORa , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), and S(O) t N(R a ) 2, where t is 1 or 2, where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0067] "Halo" or "halogen" refers to a bromo, chloro, fluoro, or iodo substituent.

[0068] "Fluoroalkyl" refers to an alkyl group, as defined above, substituted with one or more fluoro groups, examples of which include trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc., as defined above. The alkyl portion of the fluoroalkyl group may be optionally substituted as defined above for alkyl groups.

[0069] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring group containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise stated in the specification, the heterocyclyl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and may contain fused or bridged ring systems. The heteroatoms in the heterocyclyl group may be optionally oxidized. One or more nitrogen atoms, if present, may be optionally quaternized. The heterocyclyl group may be partially or fully saturated. The heterocyclyl may be attached to the remainder of the molecule through any one atom in the ring. Examples of such heterocyclyl groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxothiomorpholinyl, and 1,1 dioxothiomorpholinyl. Unless stated otherwise in the specification, the term "heterocyclyl" is intended to include heterocyclyl groups as defined above, optionally substituted by one or more substituents selected from the following substituents: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b-OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and R b -S(O) t N(R a )2, where t is 1 or 2, where R aare each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); R b are each independently a direct bond or a straight or branched chain alkylene or alkenylene; R c is a straight or branched chain alkylene or alkenylene, further wherein, unless otherwise specified, each of the above substituents is unsubstituted.

[0070] "N-heterocyclyl" or "N-linked heterocyclyl" refers to a heterocyclyl group as defined above that contains at least one nitrogen atom and the point of attachment of the heterocyclyl group to the rest of the molecule is through a nitrogen atom in the heterocyclyl group. N-heterocyclyl groups may be optionally substituted as described above for heterocyclyl groups. Examples of such N-heterocyclyl groups include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0071] "C-heterocyclyl" or "C-linked heterocyclyl" refers to a heterocyclyl group as defined above that contains at least one heteroatom and the point of attachment of the heterocyclyl group to the rest of the molecule is through a carbon atom within the heterocyclyl group. The C-heterocyclyl group may be optionally substituted as described above for heterocyclyl groups. Examples of such C-heterocyclyls include, but are not limited to, 2-morpholinyl, 2-, 3-, or 4-piperidinyl, 2-piperazinyl, 2-, or 3-pyrrolidinyl, and the like.

[0072] "Heterocyclylalkyl" refers to a group of the formula -R c -heterocyclyl (where R c is an alkylene chain as defined above). When the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may optionally be attached to an alkyl group via the nitrogen atom. The alkylene chain of the heterocyclylalkyl group may optionally be substituted as defined above for an alkylene chain. The heterocyclyl moiety of the heterocyclylalkyl group may optionally be substituted as defined above for a heterocyclyl group.

[0073] "Heterocyclylalkoxy" refers to a group of the formula -OR c Heterocyclyl (where R c is an alkylene chain as defined above) and is attached via an oxygen atom. When the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may optionally be attached to an alkyl group via the nitrogen atom. The alkylene chain of the heterocyclylalkoxy group may optionally be substituted as defined above for an alkylene chain. The heterocyclyl portion of the heterocyclylalkoxy group may optionally be substituted as defined above for a heterocyclyl group.

[0074] "Heteroaryl" refers to a group derived from a 3-18 membered aromatic ring group containing 2-17 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, a heteroaryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclically delocalized (4n+2) pi-electron system that satisfies Hückel's rule. Heteroaryl includes fused or bridged ring systems. Heteroatoms in a heteroaryl group may be optionally oxidized. One or more nitrogen atoms, if present, may be optionally quaternized. The heteroaryl is bonded to the rest of the molecule through any one atom in the ring. Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzoindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6 ]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-Hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, Pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d] pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienyl). Unless otherwise stated in this specification, the term "heteroaryl" is intended to include heteroaryl groups as defined above, which may be optionally substituted with one or more substituents selected from the following substituents: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R, b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a(where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and R b -S(O) t N(R a )2, where t is 1 or 2, where R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); R b are each independently a direct bond or a straight or branched chain alkylene or alkenylene; R c is a straight or branched chain alkylene or alkenylene, further wherein, unless otherwise specified, each of the above substituents is unsubstituted.

[0075] "N-heteroaryl" refers to a heteroaryl group, as defined above, that contains at least one nitrogen atom and the point of attachment of the heteroaryl group to the rest of the molecule is through a nitrogen atom within the heteroaryl group. N-heteroaryl groups may be optionally substituted as described above for heteroaryl groups.

[0076] "C-heteroaryl" refers to a heteroaryl group, as defined above, where the point of attachment of the heteroaryl group to the rest of the molecule is through a carbon atom within the heteroaryl group. The C-heteroaryl group may be optionally substituted as described above for heteroaryl groups.

[0077] "Heteroarylalkyl" refers to a group of the formula -R c -heteroaryl (where R c is an alkylene chain as defined above). When the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl may optionally be attached to an alkyl group via the nitrogen atom. The alkylene chain of the heteroarylalkyl group may optionally be substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkyl group may optionally be substituted as defined above for a heteroaryl group.

[0078] "Heteroarylalkoxy" refers to a group of the formula -OR c Heteroaryl (where R c is an alkylene chain as defined above) and is attached via an oxygen atom. When the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl may optionally be attached to an alkyl group via the nitrogen atom. The alkylene chain of the heteroarylalkoxy group may optionally be substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkoxy group may optionally be substituted as defined above for a heteroaryl group.

[0079] Embodiments of the present disclosure are intended to include pharma- ceutically acceptable salts, tautomers, isotopic substitutions, and stereoisomers of the compounds provided herein, such as compounds of Formula I.

[0080] As used herein, the term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids and bases, and organic acids and bases. Suitable pharmaceutically acceptable base addition salts of compounds of formula I include, but are not limited to, metallic salts formed from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts formed from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Suitable non-toxic acids include, but are not limited to, acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric acid, hydrobromic acid, maleic acid, phosphoric acid, sulfuric acid, and methanesulfonic acid. Thus, specific examples of salts include hydrochloride, formate, and mesylate. Others well known in the art are described, for example, in Remington's Pharmaceutical Sciences, 18th eds., Mack Publishing, Easton PA (1990), or Remington: The Science and Practice of Pharmacy, 19th eds., Mack Publishing, Easton PA (1995).

[0081] As used herein, and unless otherwise specified, the terms "stereoisomer" and "stereoisomerically pure" refer to one stereoisomer of a particular compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center is substantially free of the other enantiomer of that compound. A stereoisomerically pure compound having two chiral centers is substantially free of other diastereomers of that compound. A typical stereoisomerically pure compound comprises more than 80% by weight of one stereoisomer of the compound and less than 20% by weight of other stereoisomers of the compound, more than 90% by weight of one stereoisomer of the compound and less than 10% by weight of other stereoisomers of the compound, more than 95% by weight of one stereoisomer of the compound and less than 5% by weight of other stereoisomers of the compound, or more than 97% by weight of one stereoisomer of the compound and less than 3% by weight of other stereoisomers of the compound. The compounds disclosed herein may have chiral centers and may exist as racemates, individual enantiomers or diastereomers, and mixtures thereof. All of these isomers, including mixtures, are included in the embodiments disclosed herein.

[0082] The use of stereomerically pure forms of the compounds disclosed herein, as well as mixtures of those forms, are also included in the embodiments disclosed herein. For example, mixtures containing equal or unequal amounts of enantiomers of a particular compound may be used in the methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques, such as chiral columns or chiral resolving agents. Examples include Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH, Tables of Resolving Agents and Optical Resolutions p.268(ELEliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN,1972);Todd,M.,Separation Of Enantiomers:Synthetic Methods(Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim Germany,2014);Toda,F.,Enantiomer Separation:Fundamentals and Practical Methods(Springer Science & Business Media, 2007); Subramanian, G. Chiral Separation Techniques: A Practical Approach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0083] "Tautomers" refer to isomers of a compound that are in equilibrium with each other. The concentration of isomers depends on the environment in which the compound is present, and may vary depending on whether the compound is a solid or in an organic solvent or aqueous solution. For example, in aqueous solution, pyrazole exhibits the isomers shown below, which are referred to as tautomers of each other. [ka]

[0084] As one of ordinary skill in the art would readily appreciate, a wide variety of functional groups and other structures may exhibit tautomerism, and all tautomers of the compounds shown in Formula I are within the scope of the present disclosure.

[0085] Not intended to be included herein are polymers or similar indefinite structures where the substituents can be defined with an infinite series of further substituents (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group which is further substituted with a substituted heteroalkyl group, etc.). Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., pentafluorinated methyl, or a heteroaryl group having two adjacent oxygen atoms in the ring). Such impermissible substitution patterns are known to those of skill in the art.

[0086] It should also be noted that the compounds disclosed herein may contain unnatural proportions of atomic isotopes at one or more atoms. For example, the compounds may contain tritium ( 3 H), iodine-125( 125 I), Sulfur-35( 35 S), or carbon-14 ( 14 It may be labeled with a radioisotope such as C, or with deuterium ( 2 H), Carbon-13( 13 C), or nitrogen-15( 15As used herein, an "isotopologue" is an isotopically enriched compound. The term "isotopically enriched" refers to an atom having an isotopic composition different from the natural isotopic composition of that atom. "Isotopically enriched" may also refer to a compound containing at least one atom having an isotopic composition different from the natural isotopic composition of that atom. The term "isotopic composition" refers to the amount of each isotope contained in an atom. Radiolabeled and isotopically enriched compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, binding assay reagents, diagnostic agents, and in vivo imaging agents. As described herein, all isotopic variations of compounds, whether radioactive or not, are intended to be included within the scope of the embodiments provided herein. In some embodiments, isotopic substitutions of the compounds disclosed herein are provided, e.g., isotopic substitutions are compounds enriched with deuterium, carbon-13, and / or nitrogen-15. As used herein, "deuterated" refers to a compound in which at least one hydrogen (H) is replaced with a deuterium (D or 2 H), i.e., the compound is deuterium-rich in at least one position.

[0087] It is understood that, independent of the stereoisomeric or isotopic composition, each compound disclosed herein may be provided in the form of any of the pharma- ceutically acceptable salts discussed herein.Similarly, it is understood that the isotopic composition may vary independently of the stereoisomeric composition of each compound mentioned herein.Furthermore, the isotopic composition is limited to the elements contained in each compound or their salts disclosed herein, but may otherwise vary independently of the choice of pharma-ceutically acceptable salt of each compound.

[0088] It should be noted that in the event of a discrepancy between a depicted structure and the name of that structure, the depicted structure shall be borne more weight.

[0089] "Treatment," as used herein, means to alleviate, in whole or in part, a disorder, disease or condition, or one or more symptoms associated with the disorder, disease or condition, or to slow or halt the further progression or worsening of the symptoms, or to alleviate or eradicate the cause of the disorder, disease or condition itself, in one embodiment, the disorder is cancer or a symptom thereof, as described herein.

[0090] "Prevention," as used herein, refers to a method of delaying and / or preventing, in whole or in part, the onset, recurrence, or spread of a disorder, disease, or condition, i.e., protecting a subject from acquiring a disorder, disease, or condition, or reducing a subject's risk of acquiring a disorder, disease, or condition. In one embodiment, the disorder is cancer or a symptom thereof, as described herein.

[0091] The term "effective amount," in reference to a compound disclosed herein, means an amount capable of treating or preventing a disorder, symptom or condition, or a symptom thereof, as disclosed herein.

[0092] The term "subject" or "patient" as used herein includes, but is not limited to, animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs, which in one embodiment are mammals, and in another embodiment are humans. In one embodiment, the subject is a human having or at risk for a CaMKK2-mediated disease, or a symptom thereof.

[0093] The mammalian CAMKK2 protein is a 66-68 kDa kinase that contains unique N- and C-terminal domains, a central serine / threonine-directed kinase domain, and a regulatory domain that includes overlapping autoinhibitory and CAM-binding regions. CAMKK2 protein is autoinhibited by sequences adjacent to the C-terminal catalytic domain and inhibits Ca 2+ / CAM binding induces a conformational change that promotes kinase activity. Once activated, CAMKK2 protein can phosphorylate CAMKIV and CAMKI, enhancing their enzymatic activity. 5'AMP-activated protein kinase alpha (AMPKα) is an additional substrate for CAMKK2 protein, and silencing CAMKK2 protein in mammalian cells almost completely abolishes AMPK activity. CAMKK2 protein can be detected in many regions of the brain, but outside the organ, CAMKK2 protein expression is less clear. In the immune system, CAMKK2 protein has only been found in myeloid cells, including hematopoietic progenitor cells, peritoneal macrophages, and bone marrow-derived macrophages. Genetic disruption of CAMKK2 protein interferes with the development and function of myeloid cells, which in turn has a significant impact on inflammatory responses.

[0094] Although various features of the invention may be described in the context of a single embodiment, such features may also be provided separately or in any suitable combination. Conversely, although the invention may, for clarity, be described herein in the context of separate embodiments, the invention may also be practiced in a single embodiment. (compound)

[0095] In one aspect, provided herein is a compound of formula I [ka] I or a pharma- ceutically acceptable salt thereof [In the formula, W is N or CX1; R1 is O or optionally substituted heteroarylene; R2 is optionally substituted aryl; X1, X2, and X3 are each independently hydrogen, halogen, or -CN; n is between 2 and 10.

[0096] In some embodiments, W is N. In other embodiments, W is CX1.

[0097] In some embodiments, X1 is hydrogen, halogen, or -CN. In some embodiments, X1 is hydrogen or halogen.

[0098] In some embodiments, X1 is hydrogen. In some embodiments, X1 is -CN.

[0099] In some embodiments, X1 is halogen. In some embodiments, X1 is fluoro, chloro or bromo. In some embodiments, X1 is fluoro. In some embodiments, X1 is chloro. In some embodiments, X1 is bromo.

[0100] In some embodiments, R 1 is O.

[0101] In some embodiments, R1 is an optionally substituted heteroarylene. In some embodiments, the optionally substituted heteroarylene contains 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, the optionally substituted heteroarylene contains 1 to 3 heteroatoms selected from N and O. In some embodiments, R1 is an optionally substituted 5- to 10-membered heteroarylene. In some embodiments, R1 is an optionally substituted 5- to 6-membered heteroarylene. In some embodiments, R1 is an optionally substituted 8- to 10-membered heteroarylene. In some embodiments, the optionally substituted heteroarylene is a monocyclic ring. In some embodiments, the optionally substituted heteroarylene is a fused bicyclic ring. In some embodiments, R1 is a pyrazolylene optionally substituted with methyl. In some embodiments, R1 is an optionally substituted pyridinylene. In some embodiments, R1 is an optionally substituted pyrazinylene, pyrimidinylene, pyridazinylene, triazinylene, quinolinylene, isoquinolinylene, quinazolinylene, quinoxalinylene, pyrrolylene, furanylene, imidazolylene, or triazolylene.

[0102] In some embodiments, R2 is an optionally substituted aryl. In some embodiments, R2 is an optionally substituted 6-10 membered aryl. In some embodiments, R2 is an optionally substituted phenyl. In some embodiments, the optionally substituted aryl is a monocyclic ring. In some embodiments, the optionally substituted aryl is a bicyclic ring. In some embodiments, R2 is an aryl optionally substituted with at least one substituent selected from alkyl, carbonyl, carbocyclyl, heterocyclyl, and heteroaryl. In some embodiments, R2 is a C1-C6 alkyl, carbonyl, C3-C6 aryl, C4-C6 aryl, C5-C6 aryl, C6-C6 aryl, C7-C6 aryl, C8-C6 aryl, C9-C6 aryl, C10-C6 aryl, C11-C6 aryl, C12-C6 aryl, C13-C6 aryl, C14-C6 aryl, C15-C6 aryl, C16-C6 aryl, C17-C6 aryl, C18-C6 aryl, C19-C6 aryl, C20-C2 aryl, C21-C2 aryl, C22-C2 aryl, C23-C2 aryl, C24-C2 aryl, C25-C2 aryl, C26-C2 aryl, C27-C2 aryl, C28-C2 aryl, C29-C2 aryl, C30-C3 aryl, C31-C3 aryl, C32-C3 aryl, C33-C3 aryl, C34-C3 aryl, C35-C3 aryl, C36-C3 aryl, C37-C3 aryl, C38-C3 aryl, C39 ... 10and aryl, optionally substituted with at least one substituent selected from carbocyclyl, 4-10 membered heterocyclyl, and 4-10 membered heteroaryl. In some embodiments, R2 is aryl, optionally substituted with C1-C3 alkyl, optionally substituted with halogen, or C3-C4 carbocyclyl. In some embodiments, R2 is aryl, optionally substituted with -CO2H or -C(O)NH2. In some embodiments, R2 is aryl, optionally substituted with C3-C5 carbocyclyl, optionally substituted with halogen. In some embodiments, R2 is aryl substituted with C3-C5 carbocyclyl. In some embodiments, R2 is aryl substituted with C5 carbocyclyl. In some embodiments, R2 is aryl substituted with -CO2H. In some embodiments, R2 is aryl substituted with C3-C5 carbocyclyl and CO2H. In some embodiments, R2 is aryl optionally substituted with C5 carbocyclyl and CO2H. In some embodiments, R2 is aryl optionally substituted with a 6-membered heterocyclyl containing a nitrogen atom. In some embodiments, R2 is aryl optionally substituted with tetrazolyl.

[0103] In some embodiments, X2 and X3 are each independently hydrogen, halogen, or -CN. In some embodiments, X2 and X3 are each independently hydrogen or halogen. In some embodiments, X2 and X3 are each hydrogen.

[0104] In some embodiments, X2 is hydrogen. In some embodiments, X2 is -CN. In some embodiments, X2 is halogen. In some embodiments, X2 is fluoro, chloro or bromo. In some embodiments, X2 is fluoro. In some embodiments, X2 is chloro. In some embodiments, X2 is bromo.

[0105] In some embodiments, X3 is hydrogen. In some embodiments, X3 is -CN. In some embodiments, X3 is halogen. In some embodiments, X3 is fluoro, chloro or bromo. In some embodiments, X3 is fluoro. In some embodiments, X3 is chloro. In some embodiments, X3 is bromo.

[0106] In some embodiments, n is 2-10. In some embodiments, n is 3-10. In some embodiments, n is 4-10. In some embodiments, n is 2-9. In some embodiments, n is 3-9. In some embodiments, n is 4-9. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10.

[0107] In some embodiments, the formula: [ka] The structure is selected from the following structures: [ka] [ka] [ka]

[0108] In some embodiments, the compound of formula I is a compound of formula IA: [ka] IA [In the formula, R1, R2, X1, X2, X3, and n are as described for formula I.

[0109] In some embodiments, the compound of formula I is a compound of formula IA-1 or formula IA-2: [ka] IA-1 [ka] IA-2 [In the formula, R2, X1, X2, X3, and n are as described for Formula I; Ring A is an optionally substituted heteroarylene.

[0110] In some embodiments, the compound of formula IB is a compound of formula IB: [ka] IB [In the formula, R1, R2, X2, X3, and n are as described for Formula I.

[0111] In some embodiments, the compound of formula IB-1 or IB-2: [ka] IB-1 [ka] IB-2 [In the formula, R2, X2, X3, and n are as described for formula I; Ring A is an optionally substituted heteroarylene.

[0112] In some embodiments, the compound of formula I is a compound of formula IC-1 or formula IC-2: [ka] IC-1 [ka] IC-2 [In the formula, W, R2, X2, X3, and n are as described for formula I; Ring A is an optionally substituted heteroarylene.

[0113] In some embodiments, the compound of formula I is a compound of formula Ia: [ka] Ia [In the formula, and n is as described for Formula I.

[0114] In some embodiments, the compound of formula I is a compound of formula Ib: [ka] Ib [In the formula, X2, X3, and n are as described in Formula I. In some embodiments, X2 and X3 are each independently H or halo. In some embodiments, X2 and X3 are each independently H, F, or Cl. In some embodiments, X2 and X3 are each independently H or F.

[0115] It is understood herein that all statements, variations, embodiments, or aspects in formula I are the same as if each statement, variation, embodiment, or aspect were described separately and individually, and, where applicable, are equally applicable and described in other formulas described herein.For example, any statement, variation, embodiment, or aspect of W in formula I provided herein may be combined with any statement, variation, embodiment, or aspect of R1, R2, X1, X2, X3, and n, and each and every combination is the same as if specifically and individually described.It is also understood that all statements, variations, embodiments, or aspects in formula I are the same as if each statement, variation, embodiment, or aspect were described separately and individually in all formulas, and, where applicable, are equally applicable and described in other formulas described herein. For example, any statement, variation, embodiment, or aspect in Formula I, where applicable, applies equally to, and is equally described in, any formula described herein, such as Formulas IA, IA-1, IA-2, IB, IB-1, IB-2, Ia, and Ib (wherein each and every statement, variation, embodiment, or aspect is separately and individually the same as if it were described in any formula).

[0116] In some embodiments, provided is a compound selected from the compounds shown in Table 1, or a pharma- ceutically acceptable salt thereof. Although some compounds described in this disclosure, including those shown in Table 1, are presented as specific stereoisomeric and / or non-stereochemical forms, it is understood that any or all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomeric or other forms of any compound disclosed herein, including the structures shown in Table 1, are described herein. [Table 1] [Table 2] or a pharma- ceutically acceptable salt thereof.

[0117] All compounds of formula I that exist in free base or free acid form can be converted into their pharma- ceutically acceptable salts by treatment with an appropriate inorganic or organic base or acid in a manner known to those skilled in the art. Salts of compounds of formula I can be converted into the free base or free acid form by standard techniques. (Synthesis method)

[0118] The compounds described herein can be synthesized by conventional organic synthesis methods and commercially available starting materials, or by methods provided herein.By way of example, but not by way of limitation, the compound of formula IC-1 can be prepared according to scheme 1 and the examples described herein.It should be noted that those skilled in the art will understand how to modify the procedures described in the illustrated schemes and examples to obtain the desired product. [ka] Scheme 1 [In the scheme, W, X2, X3, R2, and n are as defined in Formula I; R x is an alkyl group such as ethyl or methyl, X is a halogen such as Br. [ka] Scheme 2

[0023] In the scheme, X2, X3, R2, and n are as defined in formula I; R x is an alkyl group such as ethyl or methyl; X is a halogen such as Br, R y is an alkyl group such as tert-butyl].

[0119] As shown in Scheme 1, the compound of formula I where R1 is O, i.e., the compound of formula IC-1, can be synthesized as follows: quinazoline derivative A is coupled with intermediate compound B to produce intermediate compound C, which is then deprotected to form intermediate compound D, which is subsequently coupled with intermediate I to form the compound of formula IC-1.

[0120] Scheme 2 provides a method for the synthesis of compounds of formula Ib. Quinazoline derivative A' is coupled with intermediate compound B to produce intermediate compound C', which is then deprotected to form intermediate compound D', followed by coupling with intermediate I and subsequent deprotection of the ester, for example with an acid, to form compounds of formula Ib. (How to use)

[0121] In an embodiment of the disclosure, there is provided a method of modulating CAMKK2 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I. Modulation (e.g., inhibition or activation) of CAMKK2 can be assessed and demonstrated by a variety of means known in the art. Kits and commercially available assays are available to determine whether and to what extent CAMKK2 has been modulated (inhibited or activated).

[0122] In one aspect, provided herein is a method of modulating CAMKK2, comprising contacting CAMKK2 with an effective amount of a compound of formula I, or any embodiment or variation thereof. In some embodiments, the compound of formula I inhibits CAMKK2. In some embodiments, the compound of formula I causes degradation of CAMKK2.

[0123] In some embodiments, compounds of Formula I modulate the activity of CAMKK2 by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the compound of formula I reduces the activity of CANKK2 by about 1-100%, 5-100%, 10-100%, 15-100%, 20-100%, 25-100%, 30-100%, 35-100%, 40-100%, 45-100%, 50-100%, 55-100%, 60-100%, 65-100%, 70-100%, 75-100%, 80-100%, 85-100%, 90-100%, 95-100%, 100-100%, 100-100%, 110-100%, 120-100%, 130-100%, 140-100%, 150-100%, 160-100%, 170-100%, 180-100%, 190-100%, 200-100%, 210-100%, 220-100%, 230-100%, 240-100%, 250-100%, 260-100%, 270-100%, 280-100%, 290-100%, 300-100%, 310-100%, 320-100%, 330-100%, 340-100%, 350-100%, 360-100%, 370-100%, 380-100%, 390-100%, 400-100%, 410-100%, 420-100%, 430-100%, 440-100%, 450-100%, Adjust from 5~100%, 90~100%, 95~100%, 5~95%, 5~90%, 5~85%, 5~80%, 5~75%, 5~70%, 5~65%, 5~60%, 5~55%, 5~50%, 5~45%, 5~40%, 5~35%, 5~30%, 5~25%, 5~20%, 5~15%, 5~10%, 10~90%, 20~80%, 30~70%, or 40~60%.

[0124] Also provided in some embodiments within the present disclosure is a method of degrading CAMKK2 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula I. Degradation of CAMKK2 can be assessed and demonstrated by a variety of means known in the art. Commercially available assays, including kits and cellular assays, are available to determine whether and to what extent CAMKK2 has been degraded.

[0125] In one aspect, provided herein is a method of degrading CAMKK2, comprising contacting CAMKK2 with an effective amount of a compound of formula I, or any embodiment or variation thereof. In some embodiments, the compound of formula I partially degrades CAMKK2. In some embodiments, the compound of formula I completely degrades CAMKK2.

[0126] In some embodiments, the compound of formula I degrades CAMKK2 by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the compound of formula I inhibits CAMKK2 by about 1-100%, 5-100%, 10-100%, 15-100%, 20-100%, 25-100%, 30-100%, 35-100%, 40-100%, 45-100%, 50-100%, 55-100%, 60-100%, 65-100%, 70-100%, 75-100%, 80-100%, 85-100%, 90-100%, 95-100%, 100-100%, 110-100%, 120-100%, 130-100%, 140-100%, 150-100%, 160-100%, 170-100%, 180-100%, 190-100%, 210-100%, 220-100%, 230-100%, 240-100%, 250-100%, 260-100%, 270-100%, 280-100%, 290-100%, 300-100%, 310-100%, 320-100%, 330-100%, 340-100%, 350-100%, 360-100%, 370-100%, 380-100%, 390-100%, 400-100%, 400-100%, 450-100%, 500-100%, 550-100%, 600-100%, 600-100%, 600-100%, 70 Decomposes by 100%, 90-100%, 95-100%, 5-95%, 5-90%, 5-85%, 5-80%, 5-75%, 5-70%, 5-65%, 5-60%, 5-55%, 5-50%, 5-45%, 5-40%, 5-35%, 5-30%, 5-25%, 5-20%, 5-15%, 5-10%, 10-90%, 20-80%, 30-70%, or 40-60%.

[0127] In some embodiments, provided herein are methods of regulating gene transcription in a cell, comprising modulating CAMKK2 activity by exposing CAMKK2 to a compound of Formula I. In some embodiments, the methods of regulating gene transcription in a cell comprise degrading CAMKK2.

[0128] In another aspect, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula I. In some embodiments, provided herein is a method of preventing cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula I. Non-limiting examples of cancer include acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), neuroblastoma, small round blue cell tumor, glioblastoma, glioma, prostate cancer, breast cancer, bladder cancer, lung cancer, and melanoma.

[0129] In some embodiments, administering a compound of Formula I to a subject in need thereof reduces the extent of cancer in the subject (tumor size, rate of tumor growth, metastasis, etc.). In some embodiments, administering a compound of Formula I to a subject in need thereof stabilizes the cancer (prevents or slows the progression of the cancer). In some embodiments, administering a compound of Formula I to a subject in need thereof delays the onset or recurrence of the cancer. In some embodiments, administering a compound of Formula I to a subject in need thereof slows the progression of the cancer. In some embodiments, administering a compound of Formula I to a subject in need thereof goes into partial remission of the cancer. In some embodiments, administering a compound of Formula I to a subject in need thereof goes into complete remission of the cancer. In some embodiments, administering a compound of Formula I to a subject in need thereof reduces the dosage of one or more drugs required to treat the cancer. In some embodiments, administering a compound of Formula I to a subject in need thereof enhances the effectiveness of other drugs used to treat the cancer. In some embodiments, administering a compound of Formula I to a subject in need thereof slows the progression of the cancer. In some embodiments, administering a compound of Formula I to a subject in need thereof improves the quality of life of the subject with cancer. In some embodiments, administering a compound of Formula I to a subject in need thereof prolongs the survival of a subject with cancer.

[0130] In some aspects, provided herein are methods of slowing the progression of cancer in a subject, comprising administering to the subject a compound of Formula I. In some embodiments, provided herein are methods of stabilizing cancer in a subject, comprising administering to the subject a compound of Formula I. In some embodiments, the methods prevent the progression of cancer. In some embodiments, the methods slow the progression of cancer. In some embodiments, the methods provide partial or complete remission of cancer.

[0131] In another aspect, provided herein is a method of delaying the onset or recurrence of cancer in a subject, comprising administering to the subject a compound of formula I.

[0132] In a further aspect, provided herein is a method of reducing the dosage of one or more drugs required to treat cancer in a subject, comprising administering to the subject a compound of Formula I. In some embodiments, provided herein is a method of enhancing the effect of other drugs used to treat cancer in a subject, comprising administering to the subject a compound of Formula I.

[0133] Also provided herein is a method of slowing the progression of cancer in a subject, comprising administering to the subject a compound of Formula I. In some embodiments, the method improves the quality of life of a subject with cancer. In some embodiments, the method extends the survival of a subject with cancer.

[0134] In a further aspect, provided herein is a method of promoting weight loss in a subject, comprising administering to the subject a compound of formula I. In some embodiments, the method promotes fat loss and / or improves glucose sensitivity in the subject. Accordingly, in some embodiments, provided herein is a method of treating obesity in a subject, comprising administering to the subject a compound of formula I. Pharmaceutical Compositions and Routes of Administration

[0135] The compounds provided herein may be administered to a subject orally, topically, or parenterally in conventional dosage forms, such as capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions.

[0136] The compounds disclosed herein may be administered to a subject orally, topically, or parenterally in conventional formulations, such as capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions. Suitable formulations can be prepared in a commonly used manner using conventional organic or inorganic additives, such as excipients (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, or calcium carbonate), binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, or starch), disintegrants (e.g., starch, carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, or starch), and the like. starch, low-substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate, or calcium citrate), lubricants (e.g., magnesium stearate, light anhydrous silicic acid, talc, or sodium lauryl sulfate), flavors (e.g., citric acid, menthol, glycine, or orange powder), preservatives (e.g., sodium benzoate, sodium bisulfite, methylparaben, or propylparaben), stabilizers (e.g., citric acid, sodium citrate, or acetic acid), suspending agents (e.g., methylcellulose, polyvinyl pyrroliclone, or aluminum stearate), dispersing agents (e.g., hydroxypropylmethylcellulose), diluents (e.g., water), and wax bases (e.g., cocoa butter, white petrolatum, or polyethylene glycol). The effective amount of the compound of formula I in the pharmaceutical composition may be that which produces the desired effect; for example, about 0.005 to 10 mg per kg of subject body weight for unit doses in oral and parenteral administration.

[0137] The dose of the compound of formula I to be administered to a subject may vary over a rather wide range and be left to the discretion of the physician. In general, the compounds disclosed herein may be administered at a dose of about 0.001-10 mg per kg of subject body weight, 1-4 times per day, although the dose may vary appropriately depending on the age, weight, and health condition of the subject, as well as the mode of administration. In one embodiment, the dose is about 0.001-5 mg, about 0.01-5 mg, about 0.05-1 mg, about 0.1-0.75 mg, or about 0.25-0.5 mg per kg of subject body weight. In one embodiment, one dose is given per day. The dosage of the compound of formula I in any case will depend on factors such as the solubility of the active ingredient, the dosage form used, and the route of administration.

[0138] In some embodiments, the compound of formula I is administered to a subject at a dose of about 0.001 mg to 750 mg, about 0.1 to 375 mg, about 0.1 to 150 mg, about 0.1 to 75 mg, about 0.1 to 50 mg, about 0.1 to 25 mg, or about 0.1 to 10 mg per day.

[0139] In other embodiments, provided herein are unit dose formulations comprising about 0.1-500 mg, about 1-250 mg, about 1-100 mg, about 1-50 mg, about 1-25 mg, or about 1-10 mg of a compound of formula I.

[0140] In certain embodiments, provided herein are unit dose formulations comprising about 0.1 to 100 mg of a compound of formula I.

[0141] In other embodiments, provided herein are unit dose formulations comprising 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg, or 1400 mg of a compound of formula I.

[0142] Compounds of formula I may be administered once, twice, three times, four or more times per day, In certain embodiments, doses of 100 mg or less are administered as a single dose per day, and doses of more than 100 mg are administered twice per day in an amount equal to half the total daily dose.

[0143] The compound of formula I may be administered orally for convenience. In one embodiment, when administered orally, the compound of formula I is administered with food and water. In another embodiment, the compound of formula I is dispersed in water or juice (e.g., apple juice or orange juice) or any other liquid and administered orally as a solution or suspension.

[0144] The compounds disclosed herein may also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, intrarectally, mucosally, by inhalation, or topically to the ear, nose, eye, or skin. The mode of administration is at the discretion of the physician and may depend in part on the site of the condition.

[0145] In one embodiment, provided herein is a capsule comprising a compound of formula I, the capsule containing no additional carriers, excipients, or vehicles.

[0146] In another embodiment, provided herein is a composition comprising an effective amount of a compound of Formula I and a pharma- ceutically acceptable carrier or vehicle, where the pharma- ceutically acceptable carrier or vehicle may comprise an excipient, a diluent, or a mixture thereof. In one embodiment, the composition is a pharmaceutical composition.

[0147] The compositions may be in the form of tablets, chewable tablets, capsules, liquids, injections, lozenges, suppositories, suspensions, and the like. The compositions may be formulated to contain a daily dose or a suitable fraction of a daily dose in a dosage unit, such as a single tablet, a single capsule, or a suitable amount of liquid. In one embodiment, the liquid is prepared from a water-soluble salt, such as a hydrochloride salt. Generally, all compositions are prepared according to methods well known in pharmaceutical chemistry. Capsules are prepared by mixing a compound of formula I with a suitable carrier or diluent and filling a capsule with the appropriate amount of the mixture. Examples of typical carriers and diluents include, but are not limited to, inert powdered substances such as starch, which can be of various types, powdered cellulose, especially crystalline cellulose and microcrystalline cellulose, sugars such as fructose, mannitol, and sucrose, grain flours and similar edible powders, and the like.

[0148] Tablets can be prepared by direct compression, wet granulation, or dry granulation. These formulations usually contain not only the compound, but also diluents, binders, lubricants, and disintegrants. Typical diluents include various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride, and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders include materials such as starch, gelatin, and sugars such as lactose, fructose, glucose, and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine, and the like. Polyethylene glycol, ethylcellulose, and waxes can also serve as binders.

[0149] Lubricants may be necessary in tablet formulations to prevent colorants from sticking to the tablet and punch. The lubricants may be selected from slippery solids such as talc, magnesium stearate, calcium stearate, stearic acid, and hydrogenated vegetable oils. Tablet disintegrants are substances that swell upon absorption of water to break the tablet and release the compound. Disintegrants include starches, clays, cellulose, algins, and gums. More specifically, by way of example, corn starch, potato starch, methylcellulose, agar, bentonite, wood cellulose, natural sponge powder, cation exchange resins, alginic acid, guar gum, citrus syrup, and carboxymethylcellulose may be used as well as sodium lauryl sulfate. Tablets may be coated with sugar as a flavor and sealant, or with a film-forming protective agent to modify the dissolution properties of the tablet. The composition may also be formulated as a chewable tablet, for example, using substances such as mannitol in the formulation process.

[0150] When it is desired to administer the compound of formula I as a suppository, typical bases can be used. Cocoa butter is a traditional suppository base, and the melting point can be raised slightly by adding waxes. Water-miscible suppository bases, including polyethylene glycols of various molecular weights, are commonly used.

[0151] The effect of the compound of formula I can be delayed or sustained by suitable formulation. For example, pellets of the compound of formula I that dissolve slowly can be prepared and included in tablets or capsules, or incorporated as a slow-release implantable device. The technique also includes preparing pellets with different dissolution rates and filling capsules with a mixture of the pellets. The tablet or capsule can be coated with a film that prevents dissolution for a foreseeable period of time. Even for injections, the duration of effect can be extended by dissolving or suspending the compound of formula I in an oily or emulsion vehicle that has the effect of delaying dispersion in serum.

[0152] It is understood that the pharmaceutical compositions described herein may contain mixtures of compounds of Formula I, including racemic mixtures of any of the compounds described herein. EXAMPLES

[0153] The following examples are presented by way of non-limiting illustration. Compounds are named using an automatic naming tool provided in ChemBiodraw Ultra (Cambridgesoft), which generates systematic names based on chemical structures, with stereochemistry following the Cahn-Ingold-Prelog precedence rules. Those skilled in the art can modify the procedures described in the illustrated examples to obtain the desired products.

[0154] Salts of the compounds described herein can be prepared by standard methods such as including an acid (e.g., TFA, formic acid, or HCl) in the mobile phase during chromatographic purification or by stirring the product after chromatographic purification with an acidic solution (e.g., hydrochloric acid).

[0155] The following abbreviations may be relevant to this application: List of abbreviations [Table 3] Synthesis Examples

[0156] The following examples provide the synthesis of compounds of Formula Ia where n is 4-9. Example S1: Synthesis of intermediate compound I-1. [ka]

[0157] Step 1: Synthesis of 4-(4-methylthiazol-5-yl)benzonitrile. [ka] Two batches: To a solution of 4-bromobenzonitrile (300 g, 1.65 mol) in N,N-dimethylacetamide (3000 mL) was added 4-methylthiazole (180 g, 1.81 mol) and potassium acetate (323 g, 3.30 mol). Palladium acetate (18.5 g, 82.4 mol) was added to the reaction mixture under nitrogen atmosphere. The reaction mixture was stirred at 150° C. for 5 hours. The reaction was completed by LCMS (Rt(product)=1.27 min). The reaction mixture was diluted with water (4000 mL) and extracted with ethyl acetate (4000 mL×2). The organic layers were combined, washed with saturated brine (2000 mL), dried over sodium sulfate, filtered and concentrated. The crude product was washed with (petroleum ether / ethyl acetate, 10:1, 1500 mL×3), the reaction mixture was filtered, and the filtrate was concentrated to give 4-(4-methylthiazol-5-yl)benzonitrile (590 g, 89.4% yield) as a yellow oil.

[0158] LCMS: Rt(product) = 1.27 min.

[0159] HPLC: Rt=2.56 min, purity 88% at wavelength 220 nm.

[0160] Step 2: Synthesis of [4-(4-methylthiazol-5-yl)phenyl]methanamine. [ka] Five batches: To a stirred solution of 4-(4-methylthiazol-5-yl)benzonitrile (100 g, 499 mmol) in dry tetrahydrofuran (2500 mL) at 0° C. under nitrogen atmosphere, LiAlH4 (38 g, 1.00 mol) was added in portions over 10 min. The reaction mixture was stirred at 60° C. for 3 h. The reaction was complete by LCMS (Rt(product)=0.30 min). The reaction mixture was cooled to 10° C. and water (38 mL) was added, followed by 15% NaOH solution (76 mL) and water (38 mL). The reaction mixture was then filtered and the filtrate was concentrated. The crude products were combined and water (3000 mL) was added slowly, followed by extraction with ethyl acetate (3000 mL×3). The combined organic layers were washed with saturated brine (1500 mL), dried over anhydrous Na2SO4, filtered and concentrated to give [4-(4-methylthiazol-5-yl)phenyl]methanamine (275 g, crude) as a red oil.

[0161] LCMS: Rt(product) = 0.30 min.

[0162] HPLC: Rt (product) = 2.33 min, 70% purity at wavelength 220 nm.

[0163] Step 3: Synthesis of tert-butyl (2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carboxylate. [ka] Two batches: To a solution of [4-(4-methylthiazol-5-yl)phenyl]methanamine (111.5 g, crude) in dichloromethane (1200 mL) at 25° C., HOBt (81.1 g, 600 mmol), EDCI (115 g, 600 mmol), DIEA (106 g, 818 mmol), and (2S,4R)-1-tert-butoxycarbonyl-4-hydroxypyrrolidine-2-carboxylic acid (151 g, 655 mmol) were added. The reaction mixture was stirred at 25° C. for 16 h. The reaction was complete as confirmed by LCMS (Rt(product)=1.1 min). The reaction mixtures were combined. Water (1000 mL) was added and the layers were separated. The organic layer was washed with saturated brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residues were combined and purified by silica gel chromatography (petroleum ether / ethyl acetate, 2:1 to 0:1) to give tert-butyl (2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carboxylate (110 g, 24.14% yield) as a yellow solid.

[0164] LCMS: Rt(product) = 1.1 min.

[0165] HPLC: Rt=2.33 min, purity 85% at wavelength 220 nm.

[0166] Step 4: Synthesis of (2S,4R)-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide. [ka] To a solution of tert-butyl (2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carboxylate (110 g, 263 mmol) in ethyl acetate (1.2 L) was added dropwise HCl (g) in ethyl acetate (4 M, 528 mL) at 0-5° C. The reaction mixture was stirred at 25° C. for 4 h. TLC (PE / EA=0 / 1, Rf(reactant)=0.20, Rf(product)=0.00) confirmed that only traces of starting material remained. The mixture was filtered and the filter cake was washed with ethyl acetate (200 mL). The solid was dried under vacuum to give (2S,4R)-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide hydrochloride (104 g, crude product) as a white solid.

[0167] HPLC: Rt (product) = 1.33 min, purity 92.89% at wavelength 220 nm.

[0168] Step 5: Synthesis of tert-butyl N-[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]carbamate. [ka]

[0169] To a solution of (2S,4R)-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (104 g, crude product) in dichloromethane (30 mL) was added HOBt (43.68 g, 323 mmol), EDCI (61.9 g, 323 mmol), DIEA (113.95 g, 881.69 mmol) and (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (81.6 g, 353 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 16 hours. The reaction was completed by LCMS (Rt(product)=1.28 min). Water (1000 mL) was added and the layers were separated. The organic layer was washed with saturated brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate, 2:1 to 0:1) to give tert-butyl N-[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]carbamate (70 g, 44.9% yield) as a colorless oil.

[0170] LCMS: Rt(product)=1.28 min, [M+H] + 531.50.

[0171] 1 H NMR:400 MHz DMSO-d6δ:8.98(s,1 H), 8.56(t,J=5.6 Hz,1 H), 7.44-7.38(m,4 H), 6.46(d,J=9.2 Hz,1 H), 5.14(s,1 H), 4.45-4.14(m,5 H), 3.66-3.61(m,2 H), 2.44(s,3 H), 2.04-1.89(m,2 H), 1.38(s,9 H), 0.93(s,9 H).

[0172] Step 6: Synthesis of (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide. [ka] To a solution of tert-butyl N-[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]carbamate (71.8 g, 135 mmol) in ethyl acetate (7000 mL) was added HCl(g) / ethyl acetate (4 M, 33.82 mL) at 25° C., and the reaction mixture was stirred for 2 hours at 25° C. TLC (ethyl acetate, Rf(product)=0) confirmed the completion of the reaction. The reaction mixture was filtered and the solid was washed with ethyl acetate (500 mL) and acetonitrile (300 mL) to give (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (I-1) (56.6 g, 89.6% yield, hydrochloride salt) as a pale yellow solid.

[0173] 1 H NMR:400 MHz DMSO-d6δ:9.05(s,1 H), 8.74(t,J=6.0 Hz,1 H), 8.14(d,J=4.0 Hz,3 H)7.40(s,4H), 4.57-4.53(m,1 H), 4.44-4.37(m,2 H), 4.27-4.25(m,1 H), 3.90(d,J=5.6 Hz,1 H), 3.77(d,J=11.2 Hz,1 H), 3.57-3.54(m,1 H), 2.45(s,3 H), 2.13-2.09(m,1 H), 1.90-1.86(m,1 H), 1.02(s,9 H). Example S2 Synthesis of intermediate compound, tert-butyl 2-cyclopentyl-4-(7-hydroxyquinazolin-4-yl)benzoate. [ka]

[0174] Step 1: Synthesis of 4-bromo-2-cyclopentylbenzoic acid. [ka] To a stirred solution of 4-bromo-2-fluorobenzoic acid (10.0 g, 45.66 mmol) in THF (100 mL) in a 500 mL round bottom flask was added bromo(cyclopentyl)magnesium (114.15 mL, 114.15 mmol) dropwise at 0° C. under nitrogen atmosphere. After the addition was complete, the mixture was allowed to warm to room temperature and stirred overnight. The mixture was quenched with water at 0° C. and concentrated under reduced pressure. The mixture was filtered and the filtrate was collected. The pH value of the solution was adjusted to 3 with hydrochloric acid (1 mol / L). The mixture was filtered. The filter cake was collected and concentrated under vacuum to give 4-bromo-2-cyclopentylbenzoic acid (7.25 g, 59%) as an off-white solid. MS: m / z: C 12 H 13 Calculated value for BrO2: [MH] - ;267;Measured value: [MH] - 267.

[0175] Step 2: Synthesis of tert-butyl 4-bromo-2-cyclopentyl-benzoate. [ka] A solution of 4-bromo-2-cyclopentylbenzoic acid (10 g, 37.17 mmol) in SOCl2 (50 mL, 685.47 mmol) was stirred at 75° C. for 3 h. The resulting solution was concentrated to remove excess SOCl2 to obtain 4-bromo-2-cyclopentyl-benzoyl chloride. Then, a solution of 4-bromo-2-cyclopentyl-benzoyl chloride in THF (50 mL) was added to a stirred solution of t-BuOK (5841 mg, 52.16 mmol) in THF (100 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated, the residue was added to water, extracted with EA, washed with saturated brine, and the combined organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography to obtain tert-butyl 4-bromo-2-cyclopentyl-benzoate (8 g, 66.2% yield) as an off-white solid.

[0176] Step 3: Synthesis of tert-butyl 2-cyclopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate. [ka] To a stirred solution of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (11.24 g, 44.27 mmol) in 1,4-dioxane (100 mL) was added tert-butyl 4-bromo-2-cyclopentyl-benzoate (12 g, 36.9 mmol) and Pd(dppf)Cl2 (2.5 g, 3.41 mmol) at room temperature. The reaction mixture was purged with nitrogen and stirred at 80° C. for 2 hours. The reaction mixture was concentrated and the residue was purified by silica gel column to give tert-butyl 2-cyclopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (9 g, 65.5% yield) as a white solid. 1H NMR(300 MHz,CDCl3)δ:7.81(s,1 H), 7.63(m,1 H), 7.55(m,1 H), 3.67-3.48(m,1 H), 2.07(m,2 H), 1.92-1.78(m,2 H), 1.78-1.66(m,4 H), 1.60(s,10 H), 1.35(s,12 H).

[0177] Step 4: Synthesis of 7-[(2,4-dimethoxyphenyl)methoxy]-3H-quinazolin-4-one. [ka] To a stirred solution of (2,4-dimethoxyphenyl)methanol (46 g, 274.16 mmol) in DMF (150 mL) at 0° C., 60% NaH (6.58 g, 274.16 mmol) was added in portions, and the resulting suspension was allowed to warm to room temperature over 30 min. Then, 7-fluoro-3H-quinazolin-4-one (15 g, 91.39 mmol) was added to the reaction mixture, and the resulting reaction was stirred at 100° C. for 1 h. The reaction mixture was quenched with water at 0° C., adjusted to pH 6-7 with 1N HCl, and filtered. The filter cake was collected and slurried with EA to give 7-[(2,4-dimethoxyphenyl)methoxy]-3H-quinazolin-4-one (22 g, 77.1% yield) as a white solid. MS: m / z: C 17 H 16 Calculated for N2O4: [M+H] + 313; Measured value: [M+H] + 313.

[0178] Step 5: Synthesis of 4-chloro-7-[(2,4-dimethoxyphenyl)methoxy]quinazoline. [ka] To a stirred solution of 7-[(2,4-dimethoxyphenyl)methoxy]-3H-quinazolin-4-one (22 g, 70.44 mmol) and DIEA (61.35 mL, 352.2 mmol) in toluene (150 mL) was added dropwise POCl3 (13.13 mL, 140.88 mmol) at 0° C. The resulting mixture was allowed to warm to room temperature and then stirred at 80° C. overnight. After cooling to room temperature, the mixture was azeotroped with toluene and the residue was dissolved in EA. The organic layer was washed with saturated NaHCO3 solution, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography to give 4-chloro-7-[(2,4-dimethoxyphenyl)methoxy]quinazoline (17 g, 72.9% yield) as a yellow solid. MS: m / z: C 17 H 15 Calculated for ClN2O3: [M+H] + 331; Measured value: [M+H] + 331.

[0179] Step 6: Synthesis of tert-butyl 2-cyclopentyl-4-[7-[(2,4-dimethoxyphenyl)methoxy]quinazolin-4-yl]benzoate. [ka] To a stirred solution of 4-chloro-7-[(2,4-dimethoxyphenyl)methoxy]quinazoline (22 g, 66.51 mmol) in 1,4-dioxane (200 mL) and water (40 mL) at room temperature was added Pd(dppf)Cl2CH2Cl2 (5.43 g, 6.65 mmol), Na2CO3 (21.15 g, 199.53 mmol), and tert-butyl-2-cyclopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (29.72 g, 79.81 mmol). The resulting mixture was purged with nitrogen and stirred at 60° C. for 2 hours. The reaction mixture was filtered and concentrated. The crude product was purified by silica gel chromatography to give tert-butyl 2-cyclopentyl-4-[7-[(2,4-dimethoxyphenyl)methoxy]quinazolin-4-yl]benzoate (31 g, 86.2% yield) as a pale yellow oil. MS: m / z: C 33 H 36 Calculated value for N2O5: [M+H] + 541; Measured value: [M+H] + 541.

[0180] Step 7: Synthesis of tert-butyl 2-cyclopentyl-4-(7-hydroxyquinazolin-4-yl)benzoate. [ka] To a stirred solution of tert-butyl 2-cyclopentyl-4-[7-[(2,4-dimethoxyphenyl)methoxy]quinazolin-4-yl]benzoate (31 g, 57.34 mmol) in EA (300 mL) was slowly added 2N HCl (EA) (200 mL, 57.34 mmol) at 0° C. The resulting mixture was warmed to room temperature and stirred for 3 h. After the completion of the reaction was confirmed by TLC and LCMS, the pH value of the reaction mixture was adjusted to 6-7 with saturated NaHCO3 at 0° C., extracted with EA and washed with water. The combined extracts were dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography to give tert-butyl 2-cyclopentyl-4-(7-hydroxyquinazolin-4-yl)benzoate (17 g, 75.9% yield) as a yellow solid. MS: m / z: C 24 H 26 Calculated value for N2O3: [M+H] + 391; Measured value: [M+H] + 391. Example S3: Synthesis of compound 6 (n=4). [ka]

[0181] Step 1: Synthesis of tert-butyl 2-cyclopentyl-4-[7-(7-ethoxy-7-oxo-heptoxy)quinazolin-4-yl]benzoate. [ka] To a stirred solution of tert-butyl 2-cyclopentyl-4-(7-hydroxyquinazolin-4-yl)benzoate (250 mg, 0.64 mmol) in DMF (3 mL) was added ethyl 7-bromoheptanoate (182.19 mg, 0.77 mmol) and K2CO3 (169.67 mg, 1.6 mmol) at room temperature, and the resulting mixture was stirred at 80° C. for 2 h. The reaction mixture was quenched with water and extracted with EA. The organic layer was washed with saturated brine, concentrated, and purified by column chromatography (PE / EA=5:4) to give tert-butyl 2-cyclopentyl-4-[7-(7-ethoxy-7-oxo-heptoxy)quinazolin-4-yl]benzoate (320 mg, 86.39% yield) as a pale yellow oil.

[0182] MS:m / z:C 33 H 42 Calculated value for N2O5: [M+H] + 547; Measured value: [M+H] + 547.40.

[0183] Step 2: Synthesis of 7-[4-(4-tert-butoxycarbonyl-3-cyclopentyl-phenyl)quinazolin-7-yl]oxyheptanoic acid. [ka] To a stirred solution of tert-butyl 2-cyclopentyl-4-[7-(7-ethoxy-7-oxo-heptoxy)quinazolin-4-yl]benzoate (310 mg, 0.57 mmol) in THF (3 mL) and water (0.60 mL) at room temperature, LiOH (67.9 mg, 2.84 mmol) was added, and the mixture was stirred at 60° C. for 3 h. The reaction mixture was concentrated. The residue was diluted with water, and the diluted solution was acidified to pH 5 or less with 1 M hydrochloric acid. The resulting precipitate was filtered, and the filter cake was washed with water (2×2 mL). The filter cake was dried under vacuum to give 7-[4-(4-tert-butoxycarbonyl-3-cyclopentyl-phenyl)quinazolin-7-yl]oxyheptanoic acid (290 mg, 92.39% yield) as a white solid.

[0184] MS:m / z:C 31 H 38 Calculated value for N2O5: [M+H] + 519; Measured value: [M+H] + 519.20.

[0185] Step 3: Synthesis of tert-butyl 2-cyclopentyl-4-[7-[7-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-7-oxo-heptoxy]quinazolin-4-yl]benzoate. [ka] To a stirred solution of 7-[4-(4-tert-butoxycarbonyl-3-cyclopentyl-phenyl)quinazolin-7-yl]oxyheptanoic acid (50 mg, 0.10 mmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (I-1 of Example S1) (41.51 mg, 0.10 mmol) in DMF (2 mL), HATU (54.98 mg, 0.14 mmol) and DIEA (0.04 mL, 0.29 mmol) were added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by reverse-phase flash chromatography to afford tert-butyl 2-cyclopentyl-4-[7-[7-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-7-oxo-heptoxy]quinazolin-4-yl]benzoate (85 mg, 94.68% yield) as a white oil.

[0186] MS:m / z:C 53 H 66 Calculated value for N6O7S: [M+H] +931; Measured value: [M+H] + 931.

[0187] Step 4: Synthesis of 2-cyclopentyl-4-[7-[7-oxo-7-[[rac-(1S)-2,2-dimethyl-1-[rac-(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]propyl]amino]heptoxy]quinazolin-4-yl]benzoic acid (compound 6). [ka] To a stirred solution of tert-butyl 2-cyclopentyl-4-[7-[7-oxo-7-[[rac-(1S)-2,2-dimethyl-1-[rac-(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]propyl]amino]heptoxy]quinazolin-4-yl]benzoate (80.17 mg, 0.09 mmol) in DCM (2 mL) was added TFA (1 mL) at 0° C. and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The residue was purified by Prep-HPLC to give 2-cyclopentyl-4-[7-[7-oxo-7-[[rac-(1S)-2,2-dimethyl-1-[rac-(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]propyl]amino]heptoxy]quinazolin-4-yl]benzoic acid (compound 6) (34.9 mg, 46.09% yield) as a white solid.

[0188] MS:m / z:C 49 H 58 Calculated value for N6O7S: [M+H] + 875.4; Found: [M+H] + 875.3.

[0189] 1H NMR (400 MHz methanol-d4)δ:9.21(s,1 H), 8.97(s,1 H), 8.03(d,J=9.3 Hz,1 H), 7.95(d,J=8.0 Hz,1 H), 7.83(d,J=1.7 Hz,1 H), 7.64(dd,J=8.0,1.8 Hz,1 H), 7.52-7.38(m,6 H), 4.65(s,1 H), 4.63-4.49(m,3 H), 4.37(d,J=15.5 Hz,1 H), 4.27(t,J=6.4 Hz,2 H), 3.93(d,J=10.4 Hz,2 H), 3.82(dd,J=11.0,3.8 Hz,1 H), 2.49(s,3 H), 2.42-2.24(m,2 H), 2.20(t,J=11.6 Hz,3 H), 2.10(t,J=13.4 Hz,1 H), 1.93(t,J=7.3 Hz,2 H), 1.87(s,2 H), 1.78-1.68(m,6 H), 1.59(p,J=7.1 Hz,2 H), 1.47(d,J=7.6 Hz,2 H), 1.05(s,9 H).

[0190] Prep-HPLC purification conditions: [Column: Sunfire prep C18 column, 30*150mm, 5μm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile; Flow rate: 60mL / min; Gradient: Mobile phase B 40% to 60% over 7 min; 254nm; Rt1: 6.77]. Example S4: Synthesis of compound 5 (n=5). [ka]

[0191] Step 1: Synthesis of tert-butyl 2-cyclopentyl-4-[7-(8-ethoxy-8-oxo-octoxy)quinazolin-4-yl]benzoate. [ka] A mixture of tert-butyl 2-cyclopentyl-4-(7-hydroxyquinazolin-4-yl)benzoate (2.7 g, 6.91 mmol), K2CO3 (4.77 g, 34.57 mmol), and ethyl 8-bromooctanoate (8.68 g, 34.57 mmol) in DMF (100 mL) was stirred at 80 °C for 3 h. LCMS confirmed the completion of the reaction. The reaction mixture was diluted with EA and washed with saturated brine 3-4 times. The organic layers were combined, dried over sodium sulfate, and concentrated. The product was passed through silica gel (PE / EA=1 / 1) to give tert-butyl 2-cyclopentyl-4-[7-(8-ethoxy-8-oxo-octoxy)quinazolin-4-yl]benzoate (2.5 g, 64.45% yield) as a colorless oil. MS: m / z: C 34 H 44 Calculated value for N2O5: [M+H] + 561; Measured value: [M+H] + 561.28.

[0192] Step 2: Synthesis of 8-[4-(4-tert-butoxycarbonyl-3-cyclopentyl-phenyl)quinazolin-7-yl]oxyoctanoic acid. [ka] To a stirred solution of tert-butyl 2-cyclopentyl-4-[7-(8-ethoxy-8-oxo-octoxy)quinazolin-4-yl]benzoate (2.7 g, 4.82 mmol) in methanol (60 mL) and THF (60 mL) was added a solution of LiOH (576.62 mg, 24.08 mmol) in water (30 mL). The resulting mixture was stirred at room temperature overnight. The reaction was confirmed to be complete by LCMS. The reaction was diluted with water and the pH of the diluted solution was adjusted to 4-5 with 1N HCl. The product was extracted with EA and the combined organic layers were dried over sodium sulfate and concentrated to give 8-[4-(4-tert-butoxycarbonyl-3-cyclopentyl-phenyl)quinazolin-7-yl]oxyoctanoic acid (2.5 g, 97.47% yield) as a white solid. MS: m / z: C 32 H 40Calculated value for N2O5: [M+H] + 533; Measured value: [M+H] + 533.20.

[0193] Synthesis of compound 5 Compound 5 was prepared by the following steps similar to those described in Example S3. Example S5: Synthesis of compound 4 (n=6). [ka]

[0194] Step 1: Synthesis of tert-butyl 2-cyclopentyl-4-[7-(9-ethoxy-9-oxo-nonoxy)quinazolin-4-yl]benzoate. [ka] A mixture of tert-butyl 2-cyclopentyl-4-(7-hydroxyquinazolin-4-yl)benzoate (1500 mg, 3.84 mmol), ethyl 9-bromononanoate (1121 mg, 4.23 mmol) and K2CO3 (1222 mg, 11.52 mmol) in DMF (20 mL) was stirred at 80° C. for 1.5 h. The mixture was then quenched with water and extracted with EA. The extracts were combined, dried over sodium sulfate, filtered and concentrated. The resulting oil was purified by silica gel chromatography using PE / EA (10-20%) as an eluent. The purified fractions were combined and concentrated to give tert-butyl 2-cyclopentyl-4-[7-(9-ethoxy-9-oxo-nonoxy)quinazolin-4-yl]benzoate (1820 mg, 82.4% yield) as a pale yellow oil. MS:m / z:C 35 H 46 Calculated value for N2O5: [M+H] + 575; Measured value: [M+H] + 575.40.

[0195] Step 2: Synthesis of 9-[4-(4-tert-butoxycarbonyl-3-cyclopentyl-phenyl)quinazolin-7-yl]oxynonanoic acid. [ka] To a stirred solution of tert-butyl 2-cyclopentyl-4-[7-(9-ethoxy-9-oxo-nonoxy)quinazolin-4-yl]benzoate (1820 mg, 3.17 mmol) in methanol (10 mL), THF (10 mL) and water (4 mL) at room temperature was added LiOH (379.2 mg, 15.83 mmol). The resulting solution was stirred at 50° C. for 1.5 hours. LCMS confirmed the completion of the reaction. The reaction solution was concentrated and the residue was purified by reverse phase flash chromatography (0.05% NH4HCO3 / MeCN) to give 9-[4-(4-tert-butoxycarbonyl-3-cyclopentyl-phenyl)quinazolin-7-yl]oxynonanoic acid (1340 mg, 77.4% yield) as a white solid. MS: m / z: C 33 H 42 Calculated value for N2O5: [M+H] + 547; Measured value: [M+H] + 547.25.

[0196] Step 3: Synthesis of tert-butyl 2-cyclopentyl-4-[7-[9-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-9-oxo-nonoxy]quinazolin-4-yl]benzoate. [ka] To a stirred solution of 9-[4-(4-tert-butoxycarbonyl-3-cyclopentyl-phenyl)quinazolin-7-yl]oxynonanoic acid (1340 mg, 2.45 mmol) and (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (I-1 of Example S1) (1055 mg, 2.45 mmol) in MeCN (15 mL) was added TCFH (1375 mg, 4.9 mmol) and NMI (0.97 mL, 12.26 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was then concentrated and the residue was purified by reverse phase flash chromatography (0.05% TFA / MeCN). The purified fractions were combined and concentrated to give tert-butyl 2-cyclopentyl-4-[7-[9-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-9-oxo-nonoxy]quinazolin-4-yl]benzoate (1700 mg, 72.3% yield) as a white solid. MS: m / z: C 55 H 70 Calculated value for N6O7S: [M+H] + 959; Measured value: [M+H] + 959.55.

[0197] Step 4: Synthesis of 2-cyclopentyl-4-[7-[9-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-9-oxo-nonoxy]quinazolin-4-yl]benzoic acid (4). [ka] To a stirred solution of tert-butyl 2-cyclopentyl-4-[7-[9-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-9-oxo-nonoxy]quinazolin-4-yl]benzoate (1730 mg, 1.8 mmol) in DCM (4 mL) was added TFA (1 mL, 3.92 mmol) at 0° C. The reaction mixture was stirred at room temperature for 4 hours. The reaction solution was then concentrated and purified by reverse phase flash chromatography (0.05% NH4HCO3 / MeCN, gradient: 10% MeCN to 20% MeCN over 20 min). The purified fractions were combined and concentrated to give 2-cyclopentyl-4-[7-[9-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-9-oxo-nonoxy]quinazolin-4-yl]benzoic acid (4) (982.5 mg, 59.9% yield) as a white solid. (About 300 mg of the 98% pure compound was further purified by Prep-HPLC after the first reverse phase column purification, and the two batches were combined to give 982.5 mg).

[0198] MS:m / z:C 51 H 62 Calculated value for N6O7S: [M+H] + 903; Measured value: [M+H] + 903.40.

[0199] 1H NMR (400 MHz, methanol-d4)δ:9.21(s,1 H),8.97(s,1 H), 8.03(d,J=9.2 Hz,1 H), 7.95(d,J=8.0 Hz,1 H), 7.83(d,J=1.7 Hz,1 H), 7.64(dd,J=8.0,1.8 Hz,1 H), 7.49(m,2 H), 7.48-7.37(m,4 H), 4.65(s,1 H), 4.57-4.51(m,3 H), 4.37(m,1 H), 4.26(t,J=6.4 Hz,2 H), 3.92-3.82(m,3 H), 2.49(s,3 H), 2.39-2.03(m,7 H), 1.96-1.84(m,3 H), 1.79-1.61(m,6 H), 1.59-1.51(m,3 H), 1.49-1.35(m,5 H), 1.05(s,9 H).

[0200] Prep-HPLC conditions: Column: XBridge Shield RP18 OBD Column, 30*150mm, 5μm; Mobile phase A: Water (10mmol / L NH4CO3+0.1% NH3·H2O), Mobile phase B: Acetonitrile; Flow rate: 60mL / min; Gradient: Mobile phase B from 9% to 33% over 7 min; 254 / 210nm; Rt1: 5.93. Example S6: Synthesis of compound 3 (n=7). [ka]

[0201] Step 1: Synthesis of tert-butyl 2-cyclopentyl-4-[7-(10-ethoxy-10-oxo-decoxy)quinazolin-4-yl]benzoate. [ka] To a stirred solution of tert-butyl 2-cyclopentyl-4-(7-hydroxyquinazolin-4-yl)benzoate (1000 mg, 2.56 mmol) in DMF (10 mL) was added K2CO3 (1060 mg, 7.68 mmol) and ethyl 10-bromodecanoate (857 mg, 3.07 mmol) at room temperature, followed by stirring at 80° C. for 2 h. The reaction mixture was quenched with water and extracted with EA. The extracts were combined, washed with saturated brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (PE / EA, 1:1) to give tert-butyl 2-cyclopentyl-4-[7-(10-ethoxy-10-oxo-decoxy)quinazolin-4-yl]benzoate (1400 mg, 2.38 mmol, 92.8% yield) as a pale yellow oil. MS:m / z:C 36 H 48 Calculated value for N2O5: [M+H] + 589;Actual value [M+H] + 589.

[0202] Step 2: Synthesis of 10-[4-(4-tert-butoxycarbonyl-3-cyclopentyl-phenyl)quinazolin-7-yl]oxydecanoic acid. [ka] To a stirred solution of tert-butyl 2-cyclopentyl-4-[7-(10-ethoxy-10-oxo-decoxy)quinazolin-4-yl]benzoate (1390 mg, 2.36 mmol) in methanol (5 mL), THF (5 mL) and water (2 mL) at room temperature, LiOH (113 mg, 4.72 mmol) was added and the reaction mixture was stirred at 50° C. for 1 h. The reaction mixture was concentrated, then diluted with water, and the pH value was adjusted to 4-5 with 1.0 N hydrochloric acid, and filtered to obtain 10-[4-(4-tert-butoxycarbonyl-3-cyclopentyl-phenyl)quinazolin-7-yl]oxydecanoic acid (1300 mg, 2.32 mmol, 98.2% yield) as a white solid. MS: m / z: C 34 H 44 Calculated value for N2O5: [M+H] +561; Measured value [M+H] + 561.

[0203] Step 3: Synthesis of tert-butyl 2-cyclopentyl-4-[7-[10-oxo-10-[[rac-(1S)-2,2-dimethyl-1-[rac-(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]propyl]amino]decoxy]quinazolin-4-yl]benzoate. [ka] To a solution of 10-[4-(4-tert-butoxycarbonyl-3-cyclopentyl-phenyl)quinazolin-7-yl]oxydecanoic acid (1280 mg, 2.28 mmol) in dehydrated MeCN (20 mL), TCFH (1281 mg, 4.57 mmol), NMI (0.9 mL, 11.41 mmol) and rac-(2S,4R)-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]-1-[rac-(2S)-2-amino-3,3-dimethyl-butanoyl]pyrrolidine-2-carboxamide (983 mg, 2.28 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated. The crude product was purified by reverse-phase flash chromatography (0.05% TFA / MeCN) to give tert-butyl 2-cyclopentyl-4-[7-[10-oxo-10-[[rac-(1S)-2,2-dimethyl-1-[rac-(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]propyl]amino]decoxy]quinazolin-4-yl]benzoate (1500 mg, 1.54 mmol, 67.5% yield) as a white solid. MS: m / z: C 56 H 72 Calculated value for N6O7S: [M+H] + 973; Measured value: [M+H] + 973.

[0204] Step 4: Synthesis of 2-cyclopentyl-4-[7-[10-oxo-10-[[rac-(1S)-2,2-dimethyl-1-[rac-(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]propyl]amino]decoxy]quinazolin-4-yl]benzoic acid (3). [ka] To a stirred solution of tert-butyl 2-cyclopentyl-4-[7-[10-oxo-10-[[rac-(1S)-2,2-dimethyl-1-[rac-(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]propyl]amino]decoxy]quinazolin-4-yl]benzoate (1490 mg, 1.53 mmol) in DCM (8 mL) was added TFA (4 mL, 49.11 mmol) at 0° C. and stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness under vacuum. The crude product was first purified by reverse-phase flash column chromatography and then by HP-flash chromatography to give 2-cyclopentyl-4-[7-[10-oxo-10-[[rac-(1S)-2,2-dimethyl-1-[rac-(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]propyl]amino]decoxy]quinazolin-4-yl]benzoic acid (696 mg, 0.75 mmol, 49.5% yield) as a white solid.

[0205] MS:m / z:C 52 H 64 Calculated value for N6O7S: [M+H] + 917; Measured value: [M+H] + 917.

[0206] 1H NMR (300 MHz, methanol-d4) δ:9.15(d,J=1.4 Hz,1 H), 8.87(d,J=1.3 Hz,1 H), 7.98(dd,J=9.2,1.7 Hz,1 H), 7.86(m,1 H), 7.73(m,1 H), 7.57(m,1 H), 7.52-7.28(m,6 H), 4.70-4.50(m,4 H), 4.36(m,1 H), 4.27-4.17(m,2 H), 3.92-3.76(m,3 H), 2.48(s,3 H), 2.40-2.02(m,6 H), 1.95-1.82(m,4 H), 1.80-1.50(m,8 H), 1.38(m,8H), 1.05(s,9H).

[0207] HP-Flash conditions: Column: Ultimate XB-C18 Column, 50*250mm, 10μm; Mobile phase A: Water (10mmol / L NH4HCO3); Mobile phase B: Acetonitrile; Flow rate: 90mL / min; Gradient: 10% to 50% mobile phase B over 35min; 254 / 210nm. Example S7: Synthesis of compound 2 (n=8). [ka]

[0208] Step 1: Synthesis of tert-butyl 2-cyclopentyl-4-[7-(11-methoxy-11-oxo-undecoxy)quinazolin-4-yl]benzoate. [ka] To a stirred solution of tert-butyl 2-cyclopentyl-4-(7-hydroxyquinazolin-4-yl)benzoate (200 mg, 0.51 mmol) in DMF (5 mL) was added K2CO3 (212 mg, 1.54 mmol) and methyl 11-bromoundecanoate (171 mg, 0.61 mmol) at room temperature, and the resulting solution was stirred at 80° C. for 2 h. The reaction mixture was diluted with EA and washed with saturated brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give tert-butyl 2-cyclopentyl-4-[7-(11-methoxy-11-oxo-undecoxy)quinazolin-4-yl]benzoate (270 mg, 89.5% yield) as a colorless oil. MS: m / z: C 36 H 48 Calculated value for N2O5: [M+H] + 589; Measured value: [M+H] + 589.35.

[0209] Step 2: Synthesis of 11-[4-(4-tert-butoxycarbonyl-3-cyclopentyl-phenyl)quinazolin-7-yl]oxyundecanoic acid. [ka] To a stirred solution of tert-butyl 2-cyclopentyl-4-[7-(11-methoxy-11-oxo-undecoxy)quinazolin-4-yl]benzoate (260 mg, 0.44 mmol) in methanol (3 mL), THF (3 mL) and water (1.2 mL) was added NaOH (53 mg, 1.32 mmol) at room temperature. The resulting mixture was stirred at 50° C. for 1 h. The reaction mixture was concentrated, then diluted with water, and the pH value was adjusted to 3-4 with 1.0 N HCl, and the resulting precipitate was filtered. The resulting solid was further purified by reversed-phase flash chromatography to give 11-[4-(4-tert-butoxycarbonyl-3-cyclopentyl-phenyl)quinazolin-7-yl]oxyundecanoic acid (200 mg, 78.8% yield) as a white solid. MS: m / z: C 35 H 46Calculated value for N2O5: [M+H] + 575; Measured value: [M+H] + 575.40.

[0210] Step 3: Synthesis of tert-butyl 2-cyclopentyl-4-[7-[11-oxo-11-[[rac-(1S)-2,2-dimethyl-1-[rac-(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]propyl]amino]undecoxy]quinazolin-4-yl]benzoate. [ka] To a solution of 11-[4-(4-tert-butoxycarbonyl-3-cyclopentyl-phenyl)quinazolin-7-yl]oxyundecanoic acid (90 mg, 0.16 mmol) in dehydrated MeCN (4 mL), TCFH (88 mg, 0.31 mmol), NMI (0.06 mL, 0.78 mmol) and rac-(2S,4R)-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]-1-[rac-(2S)-2-amino-3,3-dimethyl-butanoyl]pyrrolidine-2 carboxamide (67 mg, 0.16 mmol) were added. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The crude product was purified by reverse-phase flash chromatography (0.5% TFA / MeCN) to give tert-butyl 2-cyclopentyl-4-[7-[11-oxo-11-[[rac-(1S)-2,2-dimethyl-1-[rac-(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]propyl]amino]undecoxy]quinazolin-4-yl]benzoate (100 mg, 64.7% yield) as a white solid. MS: m / z: C 57 H 74 Calculated value for N6O7S: [M+H] + 988; Measured value: [M+H] + 988.

[0211] Step 4: Synthesis of 2-cyclopentyl-4-[7-[11-oxo-11-[[rac-(1S)-2,2-dimethyl-1-[rac-(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]propyl]amino]undecoxy]quinazolin-4-yl]benzoic acid (2). [ka] To a stirred solution of tert-butyl 2-cyclopentyl-4-[7-[11-oxo-11-[[rac-(1S)-2,2-dimethyl-1-[rac-(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]propyl]amino]undecoxy]quinazolin-4-yl]benzoate (90 mg, 0.09 mmol) in DCM (2 mL) was added TFA (1 mL, 12.28 mmol) at room temperature and the resulting mixture was stirred for 1 h. The reaction mixture was concentrated to dryness under vacuum. The crude product was purified by Prep-HPLC to give 2-cyclopentyl-4-[7-[11-oxo-11-[[rac-(1S)-2,2-dimethyl-1-[rac-(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]propyl]amino]undecoxy]quinazolin-4-yl]benzoic acid (2) (50.6 mg, 58.8% yield) as a white solid.

[0212] MS:m / z:C 53 H 66 Calculated value for N6O7S: [M+H] + 931; Measured value: [M+H] + 931.

[0213] 1H NMR(400 MHz,DMSO-d6)δ:9.24(s,1 H), 8.99(s,1 H), 8.57(t,J=6.1 Hz,1 H), 7.93-7.77(m,4 H), 7.62(dd,J=7.9,1.7 Hz,1 H), 7.47-7.32(m,6 H), 4.58-4.51(m,1 H), 4.43(m,2 H), 4.35(s,1 H), 4.26-4.17(m,4 H), 3.82-3.74(m,1 H), 3.71-3.60(m,2 H), 2.44(s,3 H), 2.26(m,1 H), 2.07(m,4 H), 1.90(m,1 H), 1.84-1.75(m,4 H), 1.63(m,4 H), 1.48-1.34(m,4 H), 1.26(m,10 H), 0.93(s,9 H).

[0214] Prep-HPLC conditions: Column: X Select CSH Prep C18 OBD Column, 5μm, 19*150mm; Mobile phase A: water (0.05% TFA), Mobile phase B: acetonitrile; Flow rate: 25mL / min; Gradient: 55% to 82% Mobile phase B over 7 min; 254 / 210nm; Rt1: 6.87. Example S8: Synthesis of compound 1 (n=9). [ka]

[0215] Step 1: Synthesis of tert-butyl 2-cyclopentyl-4-[7-[12-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-12-oxo-dodecoxy]quinazolin-4-yl]benzoate. [ka] A mixture of 12-[4-(4-tert-butoxycarbonyl-3-cyclopentyl-phenyl)quinazolin-7-yl]oxydodecanoic acid (75 mg, 0.13 mmol), (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (I-1 of Example S1) (60.33 mg, 0.14 mmol), TCFH (71.48 mg, 0.25 mmol) and NMI (0.06 mL, 0.76 mmol) in MeCN (5 mL) was stirred at room temperature for 2 hours. The reaction was confirmed to be complete by LCMS. The solvent was evaporated under vacuum and the crude product was purified by Prep-HPLC to give tert-butyl 2-cyclopentyl-4-[7-[12-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-12-oxo-dodecoxy]quinazolin-4-yl]benzoate (90 mg, 70.56% yield) as a brown solid. MS: m / z: C 58 H 76 Calculated value for N6O7S: [M+H] + 1001; Measured value: [M+H] + 1001.

[0216] Step 2: Synthesis of 2-cyclopentyl-4-[7-[12-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-12-oxo-dodecoxy]quinazolin-4-yl]benzoic acid (1). [ka] To a solution of tert-butyl 2-cyclopentyl-4-[7-[12-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-12-oxododecoxy]quinazolin-4-yl]benzoate (80 mg, 0.0800 mmol) in DCM (10 mL) was added TFA (4.5 mL) dropwise at 0° C. The resulting mixture was stirred at room temperature for 2 hours. LCMS confirmed the completion of the reaction. After removal of the solvent, the crude product was purified by Prep-HPLC to give 2-cyclopentyl-4-[7-[12-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-12-oxo-dodecoxy]quinazolin-4-yl]benzoic acid (1) (18.2 mg, 23.86% yield) as a white solid.

[0217] MS:m / z:C 54 H 68 Calculated value for N6O7S: [M+H] + 945.35; Found: [M+H] + 945.

[0218] 1H NMR (400 MHz, DMSO-d6)δ:9.23(s,1 H), 8.97(s,1 H), 8.55(t,J=6.2 Hz,1 H), 7.92(d,J=9.3 Hz,1 H), 7.86-7.78(m,2 H), 7.75(d,J=1.7 Hz,1 H), 7.61(dd,J=7.9,1.7 Hz,1 H), 7.45-7.33(m,6 H), 5.11(s,1 H), 4.54(d,J=9.4 Hz,1 H), 4.48-4.38(m,2 H), 4.34(s,1 H), 4.25-4.17(m,3 H), 3.82-3.73(m,1 H), 3.71-3.59(m,2 H), 2.44(s,3 H), 2.99-2.22(m,1 H), 2.14-2.01(m,4 H), 1.93-1.85(m,1 H), 1.79(q,J=5.9,5.0 Hz,4 H), 1.69-1.56(m,4 H), 1.53-1.41(m,4 H), 1.36-1.19(m,12 H), 0.92(s,9 H).

[0219] Prep-reversed phase flash chromatography conditions: [Column: XBridge Shield RP18 OBD Column, 30*150mm, 5μm; Mobile phase A: water (10mmol / L NH4CO3+0.1% NH3·H2O), Mobile phase B: acetonitrile; Flow rate: 60mL / min; Gradient: Mobile phase B from 20% to 49% over 7 min; 254 / 220nm]. Biological Examples Example B1: Efficacy and potency determination of test compounds to degrade enhanced ProLabel (ePL) tagged CAMKK2 stably expressed in 293T cells.

[0220] CAMKK2 Degradation Assay The cell line 293T was generated by lentiviral infection with pCDH-ePL-CAmkk2 and stable integrants were selected with 1 μg / mL puromycin. Cells were dispensed into 384-well plates pre-spotted with serially diluted test compounds. After 24 hours of incubation, degradation was stopped by adding DiscoverX InCELL Hunter Detection reagent.

[0221] 50 nL of DMSO containing experimental compounds was dispensed into 384-well plates (Corning #3570) using an acoustic transfer system (ATS acoustic transfer system EDC Biosystems) with 10 three-fold dilutions starting at 5 mM. 400 ePL CAMKK2 293T cells were dispensed into each well in 25 μL of medium (RPMI 1640 + 10% heat inactivated FBS). The assay plate was incubated at 37°C under 5% CO2 for 24 hours. The plate was kept at room temperature for 30 minutes, after which 25 μL of InCELL Hunter Detection Reagent Working Solution (Cat. No. 96-0002, DiscoverX, Fremont, CA) was added. The plate was incubated at room temperature for 30 minutes, and then luminescence was read in the dark on a PHERAstar reader (BMG LABTECH, Cary, NC). Data were normalized and fitted using Activity Base (IDBS, Alameda, Calif.) as described below.

[0222] The percentage of CAMKK2 levels (PoC) was determined using the luminescence signal in compound-treated wells and normalized to the PoC of the DMSO control and the PoC of the control in which luciferase activity was completely inhibited. 50 and decomposition Y min A four-parameter logistic model (sigmoidal dose-response model, Equation 1) was used to determine the association between the RR and the risk of AE. PoC=A+(100-A) / (1+(C / x)^D)(Equation 1) [In the formula, C is CAMKK2 resolution EC 50 where D is the correlation coefficient and A is Y min The lower limit is reported as Y min and E.C. 50 was used to characterize compound-derived CAMKK2 degradation efficiency].

[0223] The results are shown in Table 2. Here, Y min is the minimum percentage of protein remaining, EC 50 is Y min This is the concentration that causes a 50% decrease in protein levels. [Table 4]

[0224] The present invention has been specifically described by way of examples for clarity of understanding, but the above description and examples should not be construed as limiting the scope of the present invention. The disclosures of all patent and scientific literature cited herein are expressly incorporated herein by reference in their entirety.

Claims

1. Compounds of formula Ia: 【Chemical 1】 Ia or a pharmaceutically acceptable salt thereof [wherein n is 2 to 10].

2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 4.

3. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 5.

4. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 6.

5. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 7.

6. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 8.

7. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 9.

8. A compound selected from the following structures, or a pharmaceutically acceptable salt thereof: 【Chemistry 2】 【Chemistry 3】

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

10. 10. A method for controlling gene transcription in a cell, comprising modulating calcium / calmodulin-dependent protein kinase kinase 2 (CAMKK2) activity by exposing CAMKK2 to a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

11. 10. A method for modulating calcium / calmodulin-dependent protein kinase kinase 2 (CAMKK2), comprising contacting CAMKK2 with an effective amount of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

12. 10. A pharmaceutical composition for use in treating cancer in a subject in need thereof, comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

13. 13. The pharmaceutical composition of claim 12, wherein the cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), neuroblastoma, small round blue cell tumor, glioblastoma, glioma, prostate cancer, breast cancer, bladder cancer, lung cancer, or melanoma.

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