WO2024046406A1

WO2024046406A1 - Alkylidene carbamate as kras inhibitors

Info

Publication number: WO2024046406A1
Application number: PCT/CN2023/116008
Authority: WO
Inventors: Haiqiang ZENG; Jiping Fu; Yongfeng SUN; Yan Lou; Zhiyong Yu
Original assignee: Nikang Therapeutics, Inc.
Priority date: 2022-08-31
Filing date: 2023-08-31
Publication date: 2024-03-07
Also published as: WO2024045066A1

Abstract

Provided herein are certain alkylidenyl carbamate compounds that inhibit certain K-Ras proteins and are therefore useful for the treatment of cancers mediated by such proteins. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

Description

ALKYLIDENE CARBAMATE AS KRAS INHIBITORS

Related Application

This application claims priority to, and the benefit of, International Application No. PCT/CN2022/116281, filed on August 31, 2022, the content of which is incorporated by reference herein in its entirety.

Field of the disclosure

The present disclosure provides certain alkylidene carbamate compounds that inhibit certain K-Ras proteins and are therefore useful for the treatment of cancers mediated by such proteins. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

Background

Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (KRAS) gene is a prevalent oncogene that encodes a small GTPase transductor protein called K-Ras. K-Ras can serve as a molecular switch by cycling between active GTP-bound and inactive GDP-bound forms (see Science 2001; 294: 1299–304. ) . K-Ras signaling is activated by RAS guanine nucleotide exchange factors (GEFs) , e.g., Son of Sevenless homologue (SOS) protein, that facilitate the GDP to GTP exchange of K-Ras (see Curr Biol 2005; 15: 563–74. ) . The interaction between K-Ras and GTPase-activating proteins (GAPs) such as p120GAP and neurofibromin, potentiates K-Ras intrinsic GTPase activity and accelerates GTP hydrolysis and diminishing K-Ras signaling (see Curr. Biol. 2005; 15: 563–74. ) .

K-Ras plays a crucial role in the regulation of cell proliferation, differentiation and survival by signaling through several major downstream pathways, including the MAPK, the PI3K and the Ral-GEFs pathways (see Lung Cancer 2018; 124: 53–64) , among them the MAPK pathway is the best characterized (see Mol. Cell Biol. 1995; 15: 6443–6453. ) . K-Ras-GTP binds to and activates RAF kinases, which phosphorylates MEK and subsequently phosphorylates ERK. Phospho-ERK can further activate downstream cytosolic proteins and which then translocate to the nucleus to drive the expression of diverse genes, propagating the growth signal.

PI3K pathway is also involved in RAS-mediated tumorigenesis (see Cell 2007; 129: 957–968. ) . Upon activation by K-Ras-GTP, PI3K phosphorylates PIP2 to form PIP3, activates PDK1 and then phosphorylates AKT. pAKT yields phosphorylation of several physiological substrates, e.g., mTOR, FOXO and NF-κB that promote metabolism, cell-cycle progression, resistance to apoptosis, cell survival and migration. The Ral-GEFs signaling pathway plays a key role in RAS-mediated oncogenesis as well (see Proc. Natl. Acad. Sci. U.S.A. 1994; 91: 11089–11093. ) . The K-Ras effector, RALGDS, stimulates the RAS family RAL-A/B small GTPases for the subsequent signaling cascades. RALGDS can also promote the JNK pathway to stimulate transcription of pro-survival and cell-cycle progression genes for cell proliferation and survival.

KRAS gene is the most frequently mutated oncogene in human cancer. KRAS mutations are associated with poor clinical outcome and found at high frequency in pancreatic cancer (～90%) , colorectal cancer (～44%) and non-small-cell lung cancer (NSCLC) (～29%) (see Cancer Discov. 2021; 11: 1–16) . KRAS mutations are also present in breast cancer, liver cancer, biliary tract malignancies, endometrial cancer, cervical cancer, bladder cancer and myeloid leukemia. The most common KRAS mutations are observed at residues G12 (77%) , G13 (10%) , and Q61 (6%) , and the most predominant KRAS variant in human malignancies is G12D (35%) , followed by G12V (29%) , G12C (21%) , G12A (7%) , G12R (5%) , and G12S (3%) (see Cancer Discov. 2021; 11: 1-16) . These mutations perturbate GTP hydrolysis of K-Ras by interfering with GAP binding/stimulation and/or reducing K-Ras intrinsic GTPase activity, resulting in constitutive activation of the protein and K-Ras signaling.

Targeting KRAS signaling has been a long pursuit in drug discovery. Among KRAS mutants, K-Ras G12C offers special opportunity, because it harbors a non-native cysteine residue, which can act as nucleophile and therefore can be targeted by covelent attachment. Several such covelent inhibitors, including AMG510, MRTX849, JNJ-74699157 and LY349944631, are in clinical trials for treating cancer patients with KRAS G12C mutation (see ACS Cent. Sci. 2020; 6: 1753-1761) . These compounds occupy a dynamic pocket in the switch II region of K-Ras thereby irreversibly locking K-Ras G12C in inactive GDP-bound state. Since KRAS mutations, including G12C, enrich predominantly active-state protein in cancer cells, sufficient residual GTPase activity and nucleotide cycling are required for effective inhibition of K-Ras by inactive state-selective drugs (see Cell 2020; 183 (4) : 850-859) . Currently, there are no molecules in clinical trial that can inhibit K-Ras G12C by binding to its active GTP form or both GTP and GDP forms. Compared to K-ras G12C mutant, other prevalent K-Ras mutants, such as G12D, do not contain non-native cysteine residue and cycle through inactive state at extremely low rate, thus making non-G12C mutant-specific drug discovery more challenging.

Given the role of K-Ras mutants in human malignancy, there is still unmet medical need for development of new treatments for cancer patients with KRAS mutations. The present disclosure fulfills this and related needs.

Summary

In a first aspect, provided is a compound of Formula (I) :

wherein:

U, V, and W are CH; or one or two of U, V, and W are N and the other of U, V, and W are CH;

R¹ is a ring of formula:

where:

one of m and n is 0, 1, or 2, and the other of m and n is 0, 1, 2, or 3;

m1, n1, m5 and n5 are independently 0, 1, or 2, provided one of m5 and n5 is at least 1;

p, q, p4 and q4 are independently 0, 1, or 2, and y is 0 or 1;

R⁶, R⁸, R¹⁰, R²⁶, and R²⁸ are independently hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, hydroxy, hydroxylalkyl, alkoxyalkyl, cyano, or cyanomethyl, provided R⁶, R¹⁰, and R²⁸ are not attached to the ring -NH-;

R⁷, R⁹, R¹¹, R²⁷, and R²⁹ are independently hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, hydroxy, hydroxylalkyl, or alkoxyalkyl, provided R⁷, R¹¹, and R²⁹ are not attached to the ring -NH-; or

when R⁶ and R⁷ are attached to the carbon atoms of the ring that are opposite or diagonal to each other, then R⁶ and R⁷ can combine to form – (CH₂) _z-where (z is 1, 2, or 3) , or -CH=CH-;

R^6a is hydrogen, deuterium, alkyl, alkylidenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, cyanomethyl, cyanoethyl, or 2-cyanovinyl, provided R^6a is not attached to the ring -NH-;

R^6b is hydrogen or alkyl, provided R^6b is not attached to the ring -NH-; or

when R^6a and R^6b are attached to the same carbon of ring (a’) , they can combine to form cycloalkylene;

R^29a and R^29b are independently hydrogen, alkyl, hydroxy, cyano, or cyanomethyl provided R^29a and R^29b are not attached to the ring -NH-;

R² is hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, or cyano, provided that R² is absent when two of U, V, and W are N;

R³ is hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, cycloalkyl, cycloalkyloxy, hydroxy, or cyano;

R⁴ is -Z-R³⁰ where Z is a bond, O, NH, N (alkyl) , or S; and R³⁰ is heterocyclylalkyl, fused heterocyclylalkyl, bicyclic heterocyclyl, bicyclic heterocyclylalkyl, fused bicyclic heterocyclyl, fused bicyclic heterocyclylalkyl, heterocyclyl fused bicyclic heterocyclyl, heterocyclyl fused bicyclic heterocyclylalkyl, tricyclic heterocyclyl, or tricyclic heterocyclylalkyl, wherein:

(1) fused heterocyclyl of fused heterocyclylalkyl is substituted with R^a, R^b, R^c, and R^c1 where R^a is alkylidenyl, deuterioalkylidenyl, haloalkylidenyl, alkoxyalkylidenyl, or =CR³¹R³² and the alkyl portion of fused heterocyclylalkyl is optionally substituted with one or two deuterium;

(2) heterocyclyl of heterocyclylalkyl and bicyclic heterocyclyl, by itself or as part of bicyclic heterocyclylalkyl, are substituted with R^d, R^e, R^f and R^f1 where R^d is alkylidenyl, deuterioalkylidenyl, haloalkylidenyl, alkoxyalkylidenyl, or =CR³³R³⁴ and the alkyl portion of heterocyclylalkyl, and bicyclic heterocyclylalkyl is optionally substituted with one or two deuterium;

(3) fused bicyclic heterocyclyl, by itself or as part of fused bicyclic heterocyclylalkyl, heterocyclyl fused bicyclic heterocyclyl, by itself or as part of heterocyclyl fused bicyclic heterocyclylalkyl, and tricyclic heterocyclyl, by itself or as part of tricyclic heterocyclylalkyl, are independently substituted with R^g, R^h, Rⁱ, and Rⁱ¹ where R^g alkylidenyl, deuterioalkylidenyl, haloalkylidenyl, alkoxyalkylidenyl, or =CR³⁵R³⁶ and the alkyl portion of fused bicyclic heterocyclylalkyl, heterocyclyl fused bicyclic heterocyclylalkyl, and tricyclic heterocyclylalkyl are optionally substituted with one or two deuterium;

R³¹, R³³, and R³⁵ are independently hydrogen, alkyl, or fluoro and R³², R³⁴, and R³⁶ are independently cyano, alkoxyalkyloxyalkyl, cycloalkyl, cycloalkylalkyl, or cycloalkylalkyloxyalkyl (where cycloalkyl, by itself or as part of cycloalkylalkyl and cycloalkylalkyloxyalkyl is optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkoxy, alkoxy, alkoxyalkyl, and hydroxy) , heterocyclyl, phenyl, or heteroaryl (where heterocyclyl, phenyl, and heteroaryl are optionally substituted with one, two, or three substituents independently selected from alkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano, and hydroxy) , or independently of each other, R³¹ and R³², R³³ and R³⁴, and R³⁵ and R³⁶ together with the carbon atom to which they are attached form cycloalkylene optionally substituted with alkyl, halo, alkoxy, or hydroxy;

R^b, R^e, and R^h are:

(i) – (Q¹) -OC (O) NR³⁹R⁴⁰ wherein:

(a) Q¹ is alkylene, R³⁹ is hydrogen, deuterium, alkyl, deuterioalkyl, haloalkyl, haloalkoxyalkyl, or alkoxyalkyl and R⁴⁰ is deuterium, deuterioalkyl, cycloalkyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, or heterocyclyl optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, haloalkyl, and haloalkoxy; or R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl wherein (a) the heterocyclyl formed together by R³⁹ and R⁴⁰ is substituted with Rⁿ, R^o, R^p, and R^q where Rⁿ and R^o are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, haloalkoxy, cyano, alkoxy and hydroxy, R^p is hydrogen, deuterium, alkylidene, deuterioalkylidene, alkenyl, alkynyl, fluoro, alkoxyalkyl, alkylcarbonyl, haloalkylcarbonyl, or alkylsulfonyl, and R^q is hydrogen, deuterium, or fluoro and (b) the bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiroheterocyclyl formed together by R³⁹ and R⁴⁰ are independently substituted with R^r, R^s, and R^t independently selected from hydrogen, deuterium, alkyl, alkylthio, halo, haloalkyl, haloalkoxy, cyano, alkoxy, and hydroxy; or

(b) Q¹ is deuterioalkylene, R³⁹ is hydrogen, deuterium, alkyl, deuterioalkyl, haloalkyl, haloalkoxyalkyl, or alkoxyalkyl and R⁴⁰ is hydrogen, deuterium, alkyl, deuterioalkyl, cycloalkyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, or heterocyclyl optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, haloalkyl, and haloalkoxy; or R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl wherein (a) heterocyclyl is substituted with R^u, R^v, R^w, and R^x where R^u and R^v are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, haloalkoxy, cyano, alkoxy and hydroxy, R^w is hydrogen, deuterium, alkylidene, deuterioalkylidene, alkenyl, alkynyl, fluoro, alkoxyalkyl, alkylcarbonyl, haloalkylcarbonyl, or alkylsulfonyl, and R^x is hydrogen, deuterium, or fluoro and (b) bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiroheterocyclyl are independently substituted with R^y, R^y1, and R^y2 independently selected from hydrogen, deuterium, alkyl, alkylthio, halo, haloalkyl, haloalkoxy, cyano, alkoxy, and hydroxy; or

(ii) – (Q²) -OR⁴¹ (wherein Q² is alkylene or deuterioalkylene and R⁴¹ is cycloalkyl, cycloalkylalkyl, haloalkoxyalkyl, heterocyclyl heterocyclcylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl (wherein each ring of R⁴¹ is substituted with R^y3, R^y4, and R^y5 independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, and nitrile) ;

R^c, R^f, and Rⁱ are independently hydrogen, deuterium, alkyl, halo, alkoxy, alkoxyalkyl, or hydroxy;

R^c1, R^f1, and Rⁱ¹ are independently selected from hydrogen, deuterium, alkyl, and halo; and

R⁵ is -Q-R³⁷ where Q is a bond, alkylene, or -C (=O) -; and R³⁷ is cycloalkyl, fused cycloalkyl, fused spirocycloalkyl, aryl, aralkyl, heteroaryl, fused heteroaryl, or heteroaralkyl wherein aryl, aryl in aralkyl, heteroaryl, fused heteroaryl, and heteroaryl in heteroaralkyl are independently substituted with R^aa, R^bb, R^cc and R^dd wherein R^aa and R^bb are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R^cc is hydrogen, alkenyl, alkynyl, cyanoalkenyl, cyanoalkynyl, or halo, and R^dd is hydrogen, alkyl, alkylthio, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or

a pharmaceutically acceptable salt thereof; provided that when R^b, R^e, and R^h are – (Q¹) -OC (O) NR³⁹R⁴⁰ where Q¹ is alkylene and R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form heterocyclyl substituted with Rⁿ, R^o, R^p, and R^q; R^a, R^d, and R^g are other than deuterioalkylidene; alkyl of fused heterocyclylalkyl, heterocyclylalkyl, bicyclic heterocyclylalkyl, fused bicyclic heterocyclylalkyl, fused bicyclic heterocyclylalkyl, heterocyclyl fused bicyclic heterocyclylalkyl, and tricyclic heterocyclylalkyl are not substituted with one or two deuterium; R^c, R^f, and Rⁱ are other than deuterium; and R^c1, R^f1, and Rⁱ¹ are hydrogen; then: (i) when R^p is fluoro, then Rⁿ and R^o are other than hydrogen; and (ii) when R^p is hydrogen, then Rⁿ, R^o and R^q are other than hydrogen.

In a second aspect, provided is a pharmaceutical composition comprising a compound of Formula (I) (or any of the embodiments thereof described herein) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

In a third aspect, provided is a method of inhibiting K-Ras, in particular K-Ras G12D, in a cell, comprising contacting the cell with a compound of Formula (I) (or any of the embodiments thereof described herein) . In one embodiment of the third aspect, the contacting is in vitro. In another embodiment of the third aspect, the contacting is in vivo.

In a fourth aspect, provided is a method of inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with a compound of Formula (I) (or any of the embodiments thereof described herein) or a pharmaceutical composition thereof as disclosed herein. In one embodiment of the fourth aspect, the contacting is in vitro. In another embodiment of the fourth aspect, the contacting is in vivo.

In a fifth aspect, provided is a method of treating cancer in a patient, preferably the patient is in need of such treatment, which method comprises administering to the patient, preferably a patient in need of such treatment, a therapeutically effective amount of a compound of Formula (I) (or any of the embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a a pharmaceutical composition thereof as disclosed herein.

In a sixth aspect, provided is a method of treating cancer associated with K-Ras, in particular K-Ras G12D, in a patient, preferably the patient is in need of such treatment, which method comprises administering to the patient, preferably a patient in need of such treatment, a therapeutically effective amount of a compound of Formula (I) (or any of the embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a a pharmaceutical composition thereof as disclosed herein.

In a seventh aspect, provided is a compound of Formula (I) , (or any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as disclosed herein for use as a medicament. In one embodiment, the medicament is useful for the treatment of cancer.

In an eighth aspect, provided is a compound of Formula (I) , (or any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as disclosed herein for use as a therapy.

In a ninth aspect, provided is a compound of Formula (I) , (or any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as disclosed herein for use in the treatment of cancer.

In a tenth aspect, provided is a compound of Formula (I) , (or any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as disclosed herein for use in the treatment of cancers associated with KRas, in particular cancers associated with K-Ras G12D.

In an eleventh aspect, provided is a compound of Formula (I) , (or any embodiments thereof described herein) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof as disclosed herein for use in inhibiting K-Ras, in particular K-Ras G12D.

In any of the aforementioned aspects involving the treatment of cancer, are further embodiments comprising administering the compound of Formula (I) (or any embodiments thereof disclosed herein) , or a pharmaceutically acceptable salt thereof in combination with at least one additional anticancer agent. When combination therapy is used, the agents can be administered simultaneously or sequentially.

Detailed Description

Definitions:

Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the following meaning:

“Alkyl” means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl, pentyl, and the like.

“Alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

“Alkenyl” means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing a double bond e.g., ethenyl, propenyl, 2-propenyl, butenyl, pentenyl, and the like.

“Alkynyl” means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing a triple bond e.g., ethynyl, propynyl, 2-propynyl, butynyl, and the like.

“Alkylamino” means a –NHR radical where R is alkyl as defined above, e.g., methylamino, ethylamino, and the like.

“Alkylthio” means a -SR radical where R is alkyl as defined above, e.g., methylthio, ethylthio, and the like.

“Alkylsulfonyl” means a -SO₂R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like.

“Alkoxy” means a -OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like.

“Alkoxyalkyl” means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with at least one alkoxy group, such as one or two alkoxy groups, as defined above, e.g., 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.

“Alkoxyalkyloxyalkyl” means a – (alkylene) -OR radical where R is alkyloxyalkyl as defined above. Examples include, but are not limited to, 2-methoxyethyloxymethyl, methoxymethoxymethyl, 1-, 2-, or 3-methoxypropyloxymethyl, 2-ethoxyethyloxymethyl, and the like.

“Alkylidenyl” means refers to a group of formula R= where R is alkyl as defined above. Examples include, but are not limited to, methylidenyl (H₂C=) , ethylidenyl (CH₃CH=) , hexylidenyl (CH₃ (CH₂) ₄CH=) , 2-propylidenyl (=C (CH₃) ₂) , and the like. For example, in the compound below:

the alkylidene group, methylidenyl, is enclosed by the box which is indicated by the arrow.

“Alkoxyalkylidenyl” means refers to a group of formula =R where R is alkoxyalkyl as defined above. Examples include, but are not limited to, methoxethylidenyl (CH₃OCH₂CH=) , ethoxyethylidenyl (C₂H₅OCH₂CH=) , 1-methoxyethylidenyl (=C (CH₃) OCH₃) , and the like. For example, in the compound below:

the alkoxyalkylidenyl group, methoxethylidenyl, is enclosed by the box which is indicated by the arrow.

“Alkylcarbonyl” means a –C (O) R radical where R is alkyl as defined above e.g., -C (O) CH₃, and the like.

“Alkoxycarbonyl” means a –C (O) OR radical where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.

“Amino” means a –NH₂ radical.

“Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl or naphthyl.

“Aralkyl” means a – (alkylene) -R radical where R is aryl as defined above. Examples include, but are not limited to, benzyl, phenethyl, and the like.

“Bicyclic heterocyclyl” means a saturated monovalent fused bicyclic ring of 8 to 12 ring atoms in which one or two ring atoms are heteroatom independently selected from N, O, and S (O) _n, where n is an integer from 0 to 2, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a –CO-group. More specifically the term bicyclic heterocyclyl includes, but is not limited to, hexahydro-1H-pyrrolizinyl, and the like.

“Bicyclic heterocyclylalkyl” means a – (alkylene) -R radical where R is bicyclic heterocyclyl as defined above. Examples include, but are not limited to, hexahydro-1H-pyrrolizinylmethyl, hexahydro-1H-pyrrolizinylethyl, and the like.

“Bridged heterocyclyl” means a saturated bicyclic ring having 6 to 9 ring atoms in which two non-adjacent ring atoms are linked by a (CRR’) n group where n is 1 to 3 and R and R’ are independently H or methyl (also may be referred to herein as “bridging” group) and further wherein one or two ring atoms, including the atoms of the bridging group, are heteroatoms independently selected from N, O, and S (O) _n, where n is an integer from 0 to 2. Examples include, but are not limited to, 6-oxa-3-azabicyclo [3.1.1] heptane-3-yl8-oxa-3-azabicyclo [3.2.1] octane-3-yl, and the like.

“Cycloalkyl” means a monocyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

“Cycloalkylene” means a monocyclic saturated divalent hydrocarbon radical of three to ten carbon atoms. Examples include, but are not limited to, 1, 1-cyclopropylene, 1, 1-cyclobutylene, 1, 1-cyclopentylene, and the like.

“Cycloalkylalkyl” means a – (alkylene) -R radical where R is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropylmethyl cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

“Cycloalkyloxy” or “cycloalkoxy” means a -OR radical where R is cycloalkyl as defined above. Examples include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

Cycloalkylalkyloxy” means a -OR radical where R is cycloalkylalkyl as defined above. Examples include, but are not limited to, cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylethyloxy, and the like.

“Cycloalkylalkyloxyalkyl” means a – (alkylene) -OR radical where R is cycloalkylalkyl as defined above. Examples include, but are not limited to, cyclopropylmethyloxymethyl, cyclobutylmethoxymethyl, and the like.

“Cyanoalkyl” means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with cyano e.g., cyanomethyl, cyanoethyl, and the like.

“Cyanoalkenyl” means an alkenyl radical as defined above where one of the hydrogen atom in the alkynyl chain is replace by a cyano. Examples include, but are not limited to, -C=C (CN) , -CH₂C=C (CN) , and the like.

“Cyanoalkynyl” means an alkynyl radical as defined above where one of the hydrogen atom in the alkynyl chain is replace by a cyano. Examples include, but are not limited to, -C≡C (CN) , -CH₂C≡C (CN) , and the like.

“Deuterium” mean refers to ²H or D.

“Deuterioalkyl” means alkyl as defined above that is substituted with one or two deuterium, e.g., CD₂, CHD, and the like.

“Deuterioalkylene” means alkylene as defined above that is substituted with one or two deuterium, e.g., CD₂, CHD, and the like.

“Deuterioalkylidenyl” means refers to a group of formula R= where R is deuterioalkyl as defined above. Examples include, but are not limited to, (D₂C=) , ethylidenyl-2, 2, 2-d3 (CD₃CH=) , For example, in the compound below:

the alkylidene group, methylidenyl-d₂, is enclosed by the box which is indicated by the arrow.

“Dialkylamino” means a –NRR’ radical where R and R’ are independently alkyl as defined above, e.g., dimethylamino, methylethylamino, and the like.

“Fused bicyclic heterocyclyl” means a saturated monovalent fused bicyclic ring of 8 to 10 ring atoms in which one or two ring atoms are heteroatoms independently selected from N, O, and S (O) _n, where n is an integer from 0 to 2, one ring atom can be -CO-, and the remaining ring atoms being C, unless stated otherwise, and where two adjacent ring atoms of the bicyclic ring are fused to two adjacent ring atoms of phenyl or a five or six membered heteroaryl, each as defined herein, unless stated otherwise. More specifically the term fused bicyclic heterocyclyl includes, but is not limited to, 2, 3-dihydro-1H-pyrrolo [2, 1-a] isoindol-9b (5H) -yl, 2, 3-dihydro-1H-pyrrolo [1, 2-a] indol-9a (9H) -yl, 1, 3b, 4, 5, 6, 8-hexahydropyrrolo [3, 2-a] pyrrolizin-3b-yl, and the like.

“Fused bicyclic heterocyclylalkyl” means a – (alkylene) -R radical where R is fused bicyclic heterocyclyl as defined above. Examples include, but are not limited to, hexahydro-1H-pyrrolizinylmethyl, hexahydro-1H-pyrrolizinylethyl, 2, 3-dihydro-1H-pyrrolo [2, 1-a] isoindol-9b (5H) -ylmethyl, 2, 3-dihydro-1H-pyrrolo [1, 2-a] indol-9a (9H) -ylmethyl, and the like.

“Fused cycloalkyl” as used herein, means cycloalkyl as defined above where two adjacent ring atoms of the cycloalkyl ring are fused to two adjacent ring atoms of phenyl or a five or six membered heteroaryl, each as defined herein, unless stated otherwise. The fused cycloalkyl can be attached at any atom of the ring. Non limiting examples of the fused cycloalkyl include bicyclo [4.1.0] hepta-1, 3, 5-triene, bicyclo [4.2.0] octa-1, 3, 5-triene, and the like.

“Fused spirocycloalkyl” means spiro cycloalkyl as defined herein where two adjacent ring atoms of the spiro cycloalkyl are fused to two adjacent ring atoms of a phenyl or a five or six membered heteroaryl, each as defined herein.

“Fused heterocyclyl” means a saturated monovalent monocyclic ring of 4 to 7 ring atoms having from one to three heteroatoms independently selected from N, O, and S (O) n where n is 0, one ring atoms can be -CO-, and the remaining ring atoms being carbon, and further wherein two adjacent ring atoms of the monocyclic ring are fused to two adjacent ring atoms of a cycloalkyl, phenyl or a five or six membered heteroaryl, each as defined herein, unless stated otherwise. The nitrogen atom (s) are optionally oxidized optionally quaternized and one or two carbon atoms of the fused ring atoms in the saturated monocyclic ring includes the two common ring vertices shared with the fused phenyl or five or six membered heteroaryl. The fused heterocyclyl can be attached at any atom of the ring. Non limiting examples of the fused heterocycloalkyl include 2, 3-dihydrobenzo [b] [1, 4] -dioxinyl, 2-oxabicyclo [3.1.0] hexanyl, indolin-2-one-1-yl, indolinyl, and the like.

“Fused heterocyclylalkyl” as used herein, means a – (alkylene) -R radical where R is fused heterocyclyl, as defined herein.

“Fused heteroaryl” means fused bicyclic heteroaryl, as defined herein, where two adjacent ring atoms of the heteroaryl ring are fused to two adjacent ring atoms of phenyl.

“Halo” means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.

“Haloalkyl” means alkyl radical as defined above, which is substituted with one or more halogen atoms, e.g., one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH₂Cl, -CF₃, -CHF₂, -CH₂CF₃, -CF₂CF₃, -CF (CH₃) ₂, and the like. When the alkyl is substituted with only fluoro, it can be referred to in this Application as fluoroalkyl.

“Haloalkylidenyl” means refers to a group of formula =R where R is haloalkyl as defined above. Examples include, but are not limited to, difluoromethylidenyl (=CF₂) , 2, 2-difluoroethylidenyl (=CHCHF₂) , 1-fluoroethylidenyl =CFCH₃) , and the like. For example, in the compound below:

the group pointed to by the arrow is the haloalkylidenyl group, difluoromethylidenyl.

“Haloalkoxy” means a –OR radical where R is haloalkyl as defined above e.g., -OCF₃, -OCHF₂, and the like. When R is haloalkyl where the alkyl is substituted with only fluoro, it is referred to in this Application as fluoroalkoxy.

“Haloalkoxyalkyl” means a – (alkylene) OR radical where R is haloalkylas defined above, e.g., trifluoromethoxymethyl, difluoromethoxymethyl, and the like.

“Haloalkylcarbonyl” means a –C (O) R radical where R is haloalkyl as defined above e.g., -C (O) CF₃, -C (O) CHF₂, and the like.

“Hydroxyalkyl” means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxy-ethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2, 3-dihydroxypropyl, 1- (hydroxymethyl) -2-hydroxyethyl, 2, 3-dihydroxybutyl, 3, 4-dihydroxybutyl and 2- (hydroxymethyl) -3-hydroxypropyl, preferably 2-hydroxyethyl, 2, 3-dihydroxypropyl, and 1- (hydroxymethyl) -2-hydroxyethyl.

“Heteroalkyl” mean alkyl radical as defined above wherein one or two carbon atoms are replaced by O, NR (R is H or alkyl) , or S, provided the heteroalkyl group is attached to the remainder of the molecule via a carbon atom, e.g., methoxymethyl, methylethylaminoethyl, and the like.

“Heteroaryl” means a monovalent monocyclic or fused bicyclic aromatic radical of 5 to 10 ring atoms, unless otherwise stated, where one or more, (in one embodiment, one, two, or three) , ring atoms are heteroatom selected from N, O, and S, the remaining ring atoms being carbon. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like. As defined herein, the terms “heteroaryl” and “aryl” are mutually exclusive. When the heteroaryl ring contains 5-or 6 ring atoms it is also referred to herein as 5-or 6-membered heteroaryl. When the heteroaryl ring is fused bicyclic aromatic radical 9-or 10 ring atoms it is also referred to herein as fused bicyclic heteroaryl.

“Heteroaralkyl” means a – (alkylene) -R radical where R is heteroaryl as defined above, e.g., pyridinylmethyl, and the like. When the heteroaryl ring in heteroaralkyl contains 5-or 6 ring atoms it is also referred to herein as 5-or 6-membered heteroaralkyl.

“Heterocyclyl” means a saturated or unsaturated monovalent monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom independently selected from N, O, and S (O) _n, where n is an integer from 0 to 2, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a –CO-group. More specifically the term heterocyclyl includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydro-pyranyl, thiomorpholino, and the like. When the heterocyclyl ring is unsaturated it can contain one or two ring double bonds provided that the ring is not aromatic and may be referred to herein as heterocycloalkenyl. When the heterocyclyl group contains at least one nitrogen atom, it is also referred to herein as heterocycloamino and is a subset of the heterocyclyl group.

“Heterocyclylalkyl” or “heterocycloalkyl” means a – (alkylene) -R radical where R is heterocyclyl ring as defined above e.g., tetraydrofuranylmethyl, piperazinylmethyl, morpholinylethyl, and the like.

“Heterocyclyl fused bicyclic heterocyclyl” means a bicyclic heterocyclyl as defined herein (preferably a bicyclic heterocyclyl of 8 to 10 ring atoms) where two adjacent ring atoms of the bicyclic heterocyclyl are fused to two adjacent ring atoms of a hetereocyclyl ring as defined herein, provided the heterocyclyl ring contains at least two heteroatoms independently selected from N, O, and S (O) _n, where n is an integer from 0 to 2. The term heterocyclyl fused bicyclic heterocyclyl includes, but is not limited to, and the like.

“Heterocyclyl fused bicyclic heterocyclylalkyl” mean – (alkylene) -R where R is heterocyclyl fused bicyclic heterocyclyl as defined above.

“Oxo, ” as used herein, alone or in combination, refers to = (O) .

“Optionally substituted aryl” means aryl as defined above, that is optionally substituted with one, two, or three substituents independently selected from alkyl, hydroxyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, alkylsulfonyl, amino, alkylamino, dialkylamino, halo, haloalkyl, haloalkoxy, and cyano. When aryl is phenyl, optionally substituted aryl is referred to herein as optionally substituted phenyl.

“Optionally substituted heteroaryl” means heteroaryl as defined above that is optionally substituted with one, two, or three substituents independently selected from alkyl, alkylsulfonyl, hydroxyl, cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, and cyano.

“Optionally substituted heterocyclyl” means heterocyclyl as defined above that is optionally substituted with one, two, or three substituents independently selected from alkyl, alkylsulfonyl, alkylcarbonyl, hydroxyl, cycloalkyl, cycloalkylalkyl, carboxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, cyanoalkyl, halo, haloalkyl, haloalkoxy, and cyano, unless stated otherwise.

“Optionally substituted heterocyclylalkyl” means – (alkylene) -R where R is optionally substituted heterocyclyl as defined above.

“Tricyclic heterocyclyl” means a saturated monovalent fused tricyclic ring of 9 to 14, preferably 12 to 14, ring atoms in which one or two ring atoms are heteroatom independently selected from N, O, and S (O) _n, where n is an integer from 0 to 2, one ring atom can be -CO-, and the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a –CO-group. The term tricyclic heterocyclyl includes, but is not limited to, and the like.

“Tricyclic heterocyclylalkyl” means a – (alkylene) -R radical where R is tricyclic heterocyclyl as defined above. Examples include, but are not limited to, and the like.

“Spiro heterocyclyl” means a saturated bicyclic monovalent ring having 6 to 10 ring atoms in which one, two, or three ring atoms are heteroatom selected from N, O, and S (O) n, where n is an integer selected from 0 to 2, the remaining ring atoms being C and the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon ( “spiro carbon” ) . Representative examples include, but are not limited to, 2, 6-diazaspiro- [3.3] heptanyl, 2, 2-dioxido-2-thiaspiro [3.3] heptan-6-yl, 2, 6-diazaspiro [3.4] octanyl, 2-azaspiro [3.4] octanyl, 2-azaspiro [3.5] -nonanyl, 2, 7-diazaspiro [4.4] nonanyl, and the like.

The present disclosure also includes protected derivatives of compounds of Formula (I) . For example, when compounds of Formula (I) contain groups such as hydroxy, carboxy, or any group containing a nitrogen atom (s) , these groups can be protected with suitable protecting groups. A comprehensive list of suitable protective groups can be found in T. W. Greene, Protective Groups in Organic Synthesis, 5^th Ed., John Wiley & Sons, Inc. (2014) , the disclosure of which is incorporated herein by reference in its entirety. The protected derivatives of compounds of the present disclosure can be prepared by methods well known in the art.

The present disclosure also includes polymorphic forms and deuterated forms of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

The term “prodrug” refers to a compound that is made more active in vivo. Certain compounds Formula (I) may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003) . Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the active compound. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the “prodrug” ) , but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound.

A “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include:

acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4, 4’-methylenebis- (3-hydroxy-2-ene-1-carboxylic acid) , 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or

salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington’s Pharmaceutical Sciences, 17^th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference in its entirety.

The compounds of Formula (I) may have asymmetric centers. Compounds of Formula (I) containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. All chiral, diastereomeric, all mixtures of chiral or diastereomeric forms, and racemic forms are within the scope of this disclosure, unless the specific stereochemistry or isomeric form is specifically indicated. It will also be understood by a person of ordinary skill in the art that when a compound is denoted as (R) stereoisomer, it may contain the corresponding (S) stereoisomer as an impurity and vice versa.

Certain compounds of Formula (I) can exist as tautomers and/or geometric isomers. All possible tautomers and cis and trans isomers, as individual forms and mixtures thereof are within the scope of this disclosure. Additionally, as used herein the term alkyl includes all the possible isomeric forms of said alkyl group albeit only a few examples are set forth. Furthermore, when the cyclic groups such as aryl is substituted, it includes all the positional isomers albeit only a few examples are set forth. Furthermore, all hydrates of a compound of Formula (I) are within the scope of this disclosure.

The compounds of Formula (I) may also contain unnatural amounts of isotopes at one or more of the atoms that constitute such compounds. Unnatural amounts of an isotope may be defined as ranging from the amount found in nature to an amount 100%of the atom in question. that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the present invention, such as a compound of Formula (I) (and any embodiment thereof disclosed herein including specific compounds) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵1, respectively. Isotopically labeled compounds (e.g., those labeled with ³H and ¹⁴C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) . In some embodiments, in compounds of Formula (I) , including in Tables 1 and 2 below one or more hydrogen atoms are replaced by ²H or ³H, or one or more carbon atoms are replaced by ¹³C-or ¹⁴C-enriched carbon. Positron emitting isotopes such as ¹⁵O, ¹³N, ¹¹C, and ¹⁵F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

A “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use.

“A pharmaceutically acceptable carrier/excipient” as used in the specification and claims includes both one and more than one such excipient.

“Spiro cycloalkyl" means a saturated bicyclic monovalent ring having 5 to 10 ring atoms in in which the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon ( "spiro carbon" ) . Unless stated otherwise, spiro cycloalkyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano. Examples include, but are not limited to, Representative examples include, but are not limited to, spiro [3.3] heptane, spiro [3.4] octane, spiro [3.5] -nonane, and the like.

The term “about, ” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean that range which would encompass ± 10%of the recited value, preferably ± 5%of the recited value, wherein the recited value and the range is included.

"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, optionally substituted aryl substituted with alkyl is intended to cover aryl that is unsubstituted and aryl that is substituted with alkyl.

Certain structures provided herein are drawn with one or more floating substituents. Unless provided otherwise or otherwise clear from the context, the substituent (s) may be present on any atom of the ring through which they are drawn, where chemically feasible and valency rules permitting. For example, in the structure of Formula (I) :

R² and R³ groups are floating substituents and can replace the hydrogen atom of any one of U, V, and W of theportion of the quinazoline ring ring when U, V, and W are CH.

The term “disease” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder, ” “syndrome, ” and “condition” (as in medical condition) , in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.

The term “combination therapy” means the administration of two or more therapeutic agents to treat a disease or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.

The term “patient” is generally synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

“Treating” or “treatment” of a disease includes:

(1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease;

(2) inhibiting the disease, i.e., delaying, arresting (i.e., stabilizing) , or reducing the development or severity of the disease or its clinical symptoms; or

(3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

In one embodiment, treating or treatment of a disease includes inhibiting the disease, i.e., delaying, arresting or reducing the development or severity of the disease or its clinical symptoms; or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

A “therapeutically effective amount” means the amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof that, when administered to a patient for treating a disease, is sufficient to affect such treatment for the disease. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated. The therapeutically effective amount of a K-ras inhibitor disclosed herein can be administered to the patient in a single dosage form or multiples thereof. For example, 600 mg dose of a K-ras inhibitor can be administered in a single 600 mg tablet or two 300 mg tablets.

The terms "inhibiting" and "reducing, " or any variation of these terms in relation of K-Ras G12D, includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, reduction of K-Ras G12D GTPase activity; a decrease of K-Ras G12D GTP binding affinity or an increase of G12D GDP binding affinity; an increase of GTP off rate or a decrease of GDP off rate; a decrease of signaling transduction molecules levels downstream in the K-Ras pathway, e.g., a decrease in pERK level; and/or a decrease of K-Ras complex binding to downstream signaling molecules compared to normal.

Representative compounds of Formula (I) are disclosed in Compound Table 1 below:

Compound Table 1

Contemplated compounds of Formula (I) are provided in Compound Table 2 below:

Compound Table 2

Embodiment A:

In further embodiments 1-158 below, the present disclosure includes:

1. In embodiment 1, provided is a compound of Formula (I) as defined in the first aspect of the Summary, or a pharmaceutically acceptable salt thereof and/or the first embodiment thereof in the Summary.

2. In embodiment 2, the compound of embodiment 1, or a pharmaceutically acceptable salt thereof, is wherein R³⁰ is fused heterocyclylalkyl where fused heterocyclyl of fused heterocyclylalkyl is substituted with R^a, R^b, R^c and R^c1 as defined in the Summary.

3. In embodiment 3, the compound of any one of embodiments 1 and 2, or a pharmaceutically acceptable salt thereof, is wherein the fused heterocyclyl of fused heterocyclylalkyl is isoindolinyl substituted with R^a, R^b, R^c and R^c1 as defined therein.

4. In embodiment 4, the compound of embodiment 1, 2 or 3, or a pharmaceutically acceptable salt thereof, is wherein R^a is alkylidene.

5. In embodiment 5, the compound of any one of embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, is wherein R^a is deuterioalkylidenyl.

6. In embodiment 6, the compound of any one of embodiments 1 to 3 and 5, or a pharmaceutically acceptable salt thereof, is wherein R^a is methylidene or methylidene-d₂.

7. In embodiment 7, the compound of any one of embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, is wherein R^a is haloalkylidenyl.

8. In embodiment 8, the compound of any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, is wherein the fused heterocyclylalkyl of R³⁰ is:

where R^a, R^b and R^c are as defined therein and R^c1 is hydrogen.

9. In embodiment 9, the compound of embodiment 1, or a pharmaceutically acceptable salt thereof, is wherein R³⁰ is heterocyclylalkyl, bicyclic heterocyclyl, or bicyclic heterocyclylalkyl, where heterocyclyl of heterocyclylalkyl and bicyclic heterocyclyl, by itself or as part of bicyclic heterocyclylalkyl are substituted with R^d, R^e, R^f, and R^f1 as defined therein.

10. In embodiment 10, the compound of embodiment 1, or a pharmaceutically acceptable salt thereof, is wherein R³⁰ is heterocyclylalkyl or bicyclic heterocyclylalkyl, where heterocyclyl of heterocyclylalkyl and bicyclic heterocyclyl of bicyclic heterocyclylalkyl are substituted with R^d, R^e, R^f, and R^f1 as defined therein and alkyl of heterocyclylalkyl and bicyclic heterocyclylalkyl is substituted with one or two deuterium.

11. In embodiment 11, the compound of any one of embodiments 1, 9, and 10, or a pharmaceutically acceptable salt thereof, is wherein R³⁰ is heterocyclylalkyl where heterocyclyl of heterocyclylalkyl is substituted with R^d, R^e, R^f, and R^f1 as defined therein (for avoidance of doubt, embodiment 11 covers heterocyclylalkyl where the alkyl of heterocyclylalkyl is substituted with one or two deuterium and is not substituted with one or two deuterium) .

12. In embodiment 12, the compound of any one of embodiments 1, 9 and 11, or a pharmaceutically acceptable salt thereof, is wherein the heterocyclylalkyl is pyrrolidin-2-ylmethyl, piperidin-2-ylmethyl, or piperidin-3-ylmethyl, preferably pyrrolidin-2-ylmethyl substituted with R^d, R^e, R^f, and R^f1 as defined therein.

13. In embodiment 13, the compound of any one of embodiments 1, 10, and 11, or a pharmaceutically acceptable salt thereof, is wherein the heterocyclylalkyl is pyrrolidin-2-ylmethyl-d2, piperidin-2-ylmethyl-d2, or piperidin-3-ylmethyl-d2, preferably pyrrolidin-2-ylmethyl-d2 substituted with R^d, R^e, R^f, and R^f1 as defined therein.

14. In embodiment 14, the compound of any one of embodiments 1, 9, and 10, or a pharmaceutically acceptable salt thereof, is wherein R³⁰ is bicyclic heterocyclalkylalkyl substituted with R^d, R^e, R^f, and R^f1 as defined therein (for avoidance of doubt, embodiment 14 covers bicyclic heterocyclylalkyl where the alkyl of bicyclic heterocyclylalkyl is substituted with one or two deuterium and is not substituted with one or two deuterium) .

15. In embodiment 15, the compound of any one of embodiments 1, 9, and 14, or a pharmaceutically acceptable salt thereof, is wherein the bicyclic heterocyclylalkyl is hexahydro-1H- pyrrolizin-7a-ylalkyl, preferably, hexahydro-1H-pyrrolizin-7a-ylmethyl, where hexahydro-1H-pyrrolizin-7a-yl is substituted with R^d, R^e, R^f, and R^f1 as defined therein.

16. In embodiment 16, the compound of any one of embodiments 1, 10, and 14, or a pharmaceutically acceptable salt thereof, is wherein the bicyclic heterocyclylalkyl is hexahydro-1H-pyrrolizin-7a-ylalkyl-d2, preferably, hexahydro-1H-pyrrolizin-7a-ylmethyl-d2, where hexahydro-1H-pyrrolizin-7a-yl is substituted with R^d, R^e, R^f, and R^f1 as defined therein.

17. In embodiment 17, the compound of any one of embodiments 1, 9, 14, and 15, or a pharmaceutically acceptable salt thereof, is wherein the bicyclic heterocyclylalkyl of R³⁰ is a ring of formula:

and is substituted with R^e, R^f, and R^f1 as defined therein, preferablyis where R^d, R^e, R^f, and R^f1 are as defined therein.

18. In embodiment 18, the compound of any one of embodiments 1, 9, 14, 15, and 17, or a pharmaceutically acceptable salt thereof, is wherein R^f1 is hydrogen and the bicyclic heterocyclylalkyl of R³⁰ is a ring of formula: where R^d, R^e, R^f, are as defined therein.

19. In embodiment 19, the compound of any one of embodiments 1, 9, 14, 15, 17, and 18, or a pharmaceutically acceptable salt thereof, is wherein the bicyclic heterocyclylalkyl of R³⁰ is a ring of formula:

preferably iswhere R^d, R^e, and R^f are as defined therein.

20. In embodiment 20, the compound of any one of embodiments 1, 10, 14, and 16, or a pharmaceutically acceptable salt thereof, is wherein the bicyclic heterocyclylalkyl of R³⁰ is a ring of formula:

substituted with R^e, R^f, and R^f1 as defined therein, preferablyis where R^d, R^e and R^f are as defined therein.

21. In embodiment 21, the compound of any one of embodiments 1, 10, 14, 16, and 20, or a pharmaceutically acceptable salt thereof, is wherein R^f1 is hydrogen and the bicyclic heterocyclylalkyl of R³⁰ is a ring of formula:

where R^d, R^e and R^f are as defined therein.

22. In embodiment 22, the compound of embodiment 1, or a pharmaceutically acceptable salt thereof, is wherein R³⁰ is fused bicyclic heterocyclyl, fused bicyclic heterocyclylalkyl, heterocyclyl fused bicyclic heterocyclyl, heterocyclyl fused bicyclic heterocyclylalkyl, tricyclic heterocyclyl, or tricyclic heterocyclylalkyl, wherein fused bicyclic heterocyclyl, by itself or as part of fused bicyclic heterocyclylalkyl, heterocyclyl fused bicyclic heterocyclyl, by itself or as part of heterocyclyl fused bicyclic heterocyclylalkyl, or tricyclic heterocyclyl, by itself or as part of tricyclic heterocyclylalkyl are independently substituted with R^g, R^h, Rⁱ and Rⁱ¹ as defined therein.

23. In embodiment 23, the compound of embodiment 1, or a pharmaceutically acceptable salt thereof, is wherein R³⁰ is fused bicyclic heterocyclylalkyl, heterocyclyl fused bicyclic heterocyclylalkyl, or tricyclic heterocyclylalkyl, wherein fused bicyclic heterocyclyl of fused bicyclic heterocyclylalkyl, heterocyclyl fused bicyclic heterocyclyl of heterocyclyl fused bicyclic heterocyclylalkyl, and tricyclic heterocyclyl of tricyclic heterocyclylalkyl are independently substituted with R^g, R^h, Rⁱ, and Rⁱ¹ as defined therein and alkyl of fused bicyclic heterocyclylalkyl, heterocyclyl fused bicyclic heterocyclylalkyl, and tricyclic heterocyclylalkyl are substituted with one or two deuterium.

24. In embodiment 24, the compound of embodiment 1 or 22, or a pharmaceutically acceptable salt thereof, is wherein R³⁰ is fused bicyclic heterocyclyl substituted with R^g, R^h, Rⁱ, and Rⁱ¹ as defined therein.

25. In embodiment 25, the compound of embodiment 1, 22, or 24, or a pharmaceutically acceptable salt thereof, is wherein the fused bicyclic heterocyclyl of R³⁰ is a ring of formula:

where ring A is phenyl or 5-or 6-membered heteroaryl and the fused bicyclic heterocyclyl is additionally substituted with R^h and Rⁱ where R^g, R^h and Rⁱ are as defined as defined therein, preferably ring A is phenyl or 5-or 6-membered heteroaryl substituted with R^h and Rⁱ as defined therein.

25a. In embodiment 25a, the compound of embodiment 1, 22, or 24, or a pharmaceutically acceptable salt thereof, is wherein the fused bicyclic heterocyclyl of R³⁰ is a ring of formula:

where ring A is phenyl, pyrazolyl, pyridinyl, or pyrimidinyl, where each ring substituted with R^h and Rⁱ as defined therein.

26. In embodiment 26, the compound of any one of embodiments 1, 22, and 23, or a pharmaceutically acceptable salt thereof, is wherein R³⁰ is fused bicyclic heterocyclylalkyl where fused bicyclic heterocyclyl of fused bicyclic heterocyclylalkyl is substituted with R^g, R^h, and Rⁱ as defined therein.

27. In embodiment 27, the compound of embodiment 1, 22, or 26, or a pharmaceutically acceptable salt thereof, is wherein fused bicyclic heterocyclylalkyl of R³⁰ is a ring of formula:

where ring A is phenyl or 5-or 6-membered heteroaryl and the fused bicyclic heterocyclyl is additionally substituted with R^h and Rⁱ where R^g, R^h and Rⁱ are as defined as defined therein.

27a. In embodiment 27a, the compound of embodiment 1, 22, 26, or 27, or a pharmaceutically acceptable salt thereof, is wherein the fused bicyclic heterocyclyl of R³⁰ is a ring of formula:

where ring A is phenyl, pyrazolyl, pyridinyl, or pyrimidinyl, each ring substituted with R^h and Rⁱ as defined therein.

28. In embodiment 28, the compound of embodiment 1, 23, or 26, or a pharmaceutically acceptable salt thereof, is wherein fused bicyclic heterocyclylalkyl of R³⁰ is a ring of formula:

28a. In embodiment 28a, the compound of embodiment 1, 23, 26, or 28, or a pharmaceutically acceptable salt thereof, is wherein the fused bicyclic heterocyclylalkyl of R³⁰ is a ring of formula:

29. In embodiment 29, the compound of any one of embodiments 1 and 22 to 28a, or a pharmaceutically acceptable salt thereof, is wherein the fused bicyclic heterocyclyl of fused bicyclic heterocyclylalkyl is 2, 3-dihydro-1H-pyrrolo [2, 1-a] isoindol-9b (5H) -yl, 2, 3-dihydro-1H-pyrrolo [1, 2-a] indol-9a (9H) -yl, 1, 3b, 4, 5, 6, 8-hexahydropyrrolo [3, 2-a] pyrrolizin-3b-yl, 1-methyl-1, 3b, 4, 5, 6, 8-hexahydropyrrolo [4, 3-a] pyrrolizin-3b-yl, 4b, 6, 7, 9-tetrahydro-5H-pyrido [3, 2-a] -pyrrolizin-4b-yl, 3, 3a, 4, 5-tetrahydro-2H-pyrano [4, 3, 2-cd] isoindol-5-yl, or 1, 2, 3, 5, 10, 10a-hexahydropyrrolo [1, 2-b] isoquinolin-10a-yl, each ring substituted with R^g, R^h, and Rⁱ as defined therein.

30. In embodiment 30, the compound of embodiment 1 or 22, or a pharmaceutically acceptable salt thereof, is wherein R³⁰ is tricyclic heterocyclyl substituted with R^g, R^h, and Rⁱ as defined therein.

31. In embodiment 31, the compound of embodiment 1 or 22, or a pharmaceutically acceptable salt thereof, is wherein R³⁰ is tricyclic heterocyclylalkyl where tricyclic heterocyclyl of tricyclic heterocyclylalkyl is substituted with R^g, R^h, and Rⁱ as defined therein.

32. In embodiment 32, the compound of embodiment 1 or 23, or a pharmaceutically acceptable salt thereof, is wherein R³⁰ is tricyclic heterocyclylalkyl where tricyclic heterocyclyl of tricyclic heterocyclylalkyl is substituted with R^g, R^h, and Rⁱ as defined therein and the alkyl of tricyclic heterocyclylalkyl is substituted with one or two deuterium.

33. In embodiment 33, the compound of any one of embodiments 1, 9, 14, 15, and 17, or a pharmaceutically acceptable salt thereof, is wherein the bicyclic heterocyclylalkyl of R³⁰ is a ring of formula:

preferably

34. In embodiment 34, the compound of any one of embodiments 1 and 9 to 33, or a pharmaceutically acceptable salt thereof, is wherein R^d and R^g are independently haloalkenyl, alkylidenyl, deuterioalkylidenyl, haloalkylidenyl, or alkoxyalkylidenyl.

35. In embodiment 35, the compound of any one of embodiments 1 and 9 to 34, or a pharmaceutically acceptable salt thereof, is wherein R^d and R^g are alkylidenyl.

36. In embodiment 36, the compound of any one of embodiments 1 and 9 to 35, or a pharmaceutically acceptable salt thereof, is wherein R^d and R^g are methylidenyl.

37. In embodiment 37, the compound of any one of embodiments 1 and 9 to 34, or a pharmaceutically acceptable salt thereof, is wherein R^d and R^g are haloalkylidenyl.

38. In embodiment 38, the compound of any one of embodiments 1, 7, 9 to 34 and 37, or a pharmaceutically acceptable salt thereof, is wherein R^a, R^d, and R^g are independently =CHF, =CF₂, =CHCH₂F, =C (CH₃) F, or =CHCHF₂.

39. In embodiment 39, the compound of any one of embodiments 1 to 3, 8, and 9 to 34, or a pharmaceutically acceptable salt thereof, is wherein R^a, R^d, and R^g are alkoxyalkylidenyl.

40. In embodiment 40, the compound of any one of embodiments 1 to 3, 8, 9 to 34, and 39, or a pharmaceutically acceptable salt thereof, is wherein R^a, R^d and R^g are independently =CH₂O (CH₂) ₂OCH₃ or =CH₂O (CH₂) ₂OC₂H₅.

41. In embodiment 41, the compound of any one of embodiments 1 and 9 to 34, or a pharmaceutically acceptable salt thereof, is wherein R^d and R^g are deuterioalkylidenyl.

42. In embodiment 42, the compound of any one of embodiments 1, 9 to 34, and 41, or a pharmaceutically acceptable salt thereof, is wherein R^d and R^g are independently =CD₂.

43. In embodiment 43, the compound of any one of embodiments 1 to 3 and 8 to 33, or a pharmaceutically acceptable salt thereof, is wherein R^a, R^d, and R^g are =CR³¹R³², =CR³³R⁴, and =CR³⁵R³⁶, respectively.

44. In embodiment 44, the compound of any one of embodiments 1 to 3, 8 to 33 and 43, or a pharmaceutically acceptable salt thereof, is wherein R³¹, R³³, and R³⁵ are hydrogen.

45. In embodiment 45, the compound of any one of embodiments 1 to 3, 8 to 33, and 43, or a pharmaceutically acceptable salt thereof, is wherein R³¹, R³³, and R³⁵ are fluoro.

46. In embodiment 46, the compound of any one of embodiments 1 to 3, 8 to 33, and 43, or a pharmaceutically acceptable salt thereof, is wherein R³¹, R³³, and R³⁵ are alkyl.

47. In embodiment 47, the compound of any one of embodiments 1 to 3, 8 to 33, 43, and 46, or a pharmaceutically acceptable salt thereof, is wherein R³¹, R³³, and R³⁵ are independently methyl, ethyl, or propyl.

48. In embodiment 48, the compound of any one of embodiments 1 to 3, 8 to 33, and 43 to 47, or a pharmaceutically acceptable salt thereof, is wherein R³², R³⁴, and R³⁶ are independently cyano, alkoxyalkyloxyalkyl, cycloalkyl, cycloalkylalkyl, or cycloalkylalkyloxyalkyl (where cycloalkyl, by itself or as part of cycloalkylalkyl, and cycloalkylalkyloxyalkyl is optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkoxy, alkoxy, alkoxyalkyl, and hydroxy) .

49. In embodiment 49, the compound of any one of embodiments 1 to 3, 8 to 33 and 43 to 48, or a pharmaceutically acceptable salt thereof, is wherein R³², R³⁴, and R³⁶ are independently cyano, methoxymethyloxymethyl, 2-methoxyethyloxymethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclopropylmethyloxymethyl, cyclobutylmethyloxymethyl, or cyclopentylmethyloxymethyl, wherein cyclopropyl, cyclobutyl or cyclopentyl, by itself or as part of cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclopropylmethyloxymethyl, cyclobutylmethyloxymethyl, and cyclopentylmethyloxymethyl, respectively, are optionally substituted with methoxy, fluoro, or methoxymethyl.

50. In embodiment 50, the compound of any one of embodiments 1 to 3, 8 to 33, and 43 to 49, or a pharmaceutically acceptable salt thereof, is wherein R³², R³⁴, R³⁶, and R³⁸ are cyano.

51. In embodiment 51, the compound of any one of embodiments 1 to 3, 8 to 33 and 43 to 49, or a pharmaceutically acceptable salt thereof, is wherein R³², R³⁴, and R³⁶ are independently methoxymethyloxymethyl or 2-methoxyethyloxymethyl.

52. In embodiment 52, the compound of any one of embodiments 1 to 3, 8 to 33 and 43 to 47, or a pharmaceutically acceptable salt thereof, is wherein R³², R³⁴, and R³⁶ are independently heterocyclyl, phenyl, or heteroaryl (where heterocyclyl, phenyl, and heteroaryl are optionally substituted with one, two, or three substituents independently selected from alkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano, and hydroxy) .

53. In embodiment 53, the compound of any one of embodiments 1 to 3, 8 to 33, 43 to 47, and 52 or a pharmaceutically acceptable salt thereof, is wherein R³², R³⁴, and R³⁶ are independently phenyl, pyrrolidinyl, furanyl, pyranyl, piperidinyl, morpholinyl, or 5-or 6-membereing heteroaryl, each ring optionally substituted with one, two, or three substituents independently selected from alkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano, and hydroxy.

54. In embodiment 54, the compound of any one of embodiments 1 to 3, 8 to 33, and 43, or a pharmaceutically acceptable salt thereof, is wherein R³¹ and R³², R³³ and R⁴, and R³⁵ and R³⁶ together with the carbon atom to which they are attached form cycloalkylene optionally substituted with alkyl, halo, alkoxy, or hydroxy.

55. In embodiment 55, the compound of any one of embodiments 1 to 3, 8 to 33, 43 and 54, or a pharmaceutically acceptable salt thereof, is wherein R³¹ and R³², R³³ and R³⁴, and R³⁵ and R³⁶ together with the carbon atom to which they are attached form cyclopropyl, cyclobutylene, or cyclopentylene, each ring optionally substituted with methyl, fluoro, or methoxy.

56. In embodiment 56, the compound of any one of embodiments 1 to 55, or a pharmaceutically acceptable salt thereof, wherein Q¹ is alkylene.

57. In embodiment 57, the compound of any one of embodiments 1 to 55, or a pharmaceutically acceptable salt thereof, is wherein Q¹ is deuterioalkyl.

58. In embodiment 58, the compound of any one of embodiments 1 to 57, or a pharmaceutically acceptable salt thereof, wherein Q¹ is methylene, ethylene, -CH (CH₃) -, -C (CH₃) ₂-, or -CD₂-.

59. In embodiment 59, the compound of any one of embodiments 1 to 56 and 58, or a pharmaceutically acceptable salt thereof, wherein Q¹ is methylene, ethylene, -CH (CH₃) -, -C (CH₃) ₂, preferably methylene.

60. In embodiment 60, the compound of any one of embodiments 1 to 55, 57, and 58, or a pharmaceutically acceptable salt thereof, wherein Q¹ is -CD₂-.

61. In embodiment 61, the compound of any one of embodiments 1 to 56 and 59, or a pharmaceutically acceptable salt thereof, wherein R³⁹ is hydrogen, deuterium, alkyl, deuterioalkyl, haloalkyl, haloalkoxyalkyl, or alkoxyalkyl and R⁴⁰ is deuterioalkyl, cycloalkyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, or heterocyclyl optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, haloalkoxy, and haloalkyl.

62. In embodiment 62, the compound of any one of embodiments 1 to 61, or a pharmaceutically acceptable salt thereof, wherein R³⁹ is hydrogen or deuterium.

63. In embodiment 63, the compound of any one of embodiments 1 to 61, or a pharmaceutically acceptable salt thereof, wherein R³⁹ is alkyl.

64. In embodiment 64, the compound of any one of embodiments 1 to 61, or a pharmaceutically acceptable salt thereof, wherein R³⁹ is haloalkyl.

65. In embodiment 65, the compound of any one of embodiments 1 to 61, or a pharmaceutically acceptable salt thereof, wherein R³⁹ is haloalkoxyalkyl.

66. In embodiment 66, the compound of any one of embodiments 1 to 61, or a pharmaceutically acceptable salt thereof, wherein R³⁹ is alkoxyalkyl.

66a. In embodiment 66a, the compound of any one of embodiments 1 to 61, or a pharmaceutically acceptable salt thereof, wherein R³⁹ is deuterioalkyl.

67. In embodiment 67, the compound of any one of embodiments 1 to 66a, or a pharmaceutically acceptable salt thereof, wherein R⁴⁰ is alkoxy.

68. In embodiment 68, the compound of any one of embodiments 1 to 66a, or a pharmaceutically acceptable salt thereof, wherein R⁴⁰ is alkoxyalkyl.

69. In embodiment 69, the compound of any one of embodiments 1 to 66a, or a pharmaceutically acceptable salt thereof, wherein R⁴⁰ is haloalkyl.

70. In embodiment 70, the compound of any one of embodiments 1 to 66a, or a pharmaceutically acceptable salt thereof, wherein R⁴⁰ is haloalkoxyalkyl.

71. In embodiment 71, the compound of any one of embodiments 1 to 66a, or a pharmaceutically acceptable salt thereof, wherein R⁴⁰ is cycloalkyl.

72. In embodiment 72, the compound of any one of embodiments 1 to 66a, or a pharmaceutically acceptable salt thereof, wherein R⁴⁰ is deuterioalkyl.

72a. In embodiment 72a, the compound of any one of embodiments 1 to 66a, or a pharmaceutically acceptable salt thereof, wherein R⁴⁰ is heterocyclyl optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, haloalkoxy, and haloalkyl.

73. In embodiment 73, the compound of any one of embodiments 1 to 60, and 66a to 72a, or a pharmaceutically acceptable salt thereof, wherein R³⁹ is hydrogen, methyl, methyl-d3, methoxyethyl, ethoxyethyl, or propoxyethyl; and R⁴⁰ is methyl-d3, cyclopropyl, 2, 2-difluoroethyl, 2, 2, 2-trifluoroethyl, 2, 2-difluoroethoxy, 2, 2, 2-trifluoroethoxy, methoxyethyl, ethoxyethyl, oxetan-3-yl, tetrahydrofuranyl, or tetrahydropyranyl.

74. In embodiment 74, the compound of any one of embodiments 1 to 56 and 59, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl wherein (a) heterocyclyl is substituted with Rⁿ, R^o, R^p, and R^q and (b) bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiroheterocyclyl are independently substituted with R^r, R^s, and R^t.

75. In embodiment 75, the compound of any one of embodiments 1 to 56, 59 and 74, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form heterocyclyl substituted with Rⁿ, R^o, R^p, and R^q.

76. In embodiment 76, the compound of any one of embodiments 1 to 56, 59 and 74, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, each ring independently substituted with R^r, R^s, and R^t.

77. In embodiment 77, the compound of any one of embodiments 1 to 56, 59, 74, and 75, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-1-yl, or homomorpholin-1-yl, each ring substituted with Rⁿ, R^o, R^p, and R^q.

77a. In embodiment 77a, the compound of any one of embodiments 1 to 56, 59, 74, 75 and 77, is wherein Rⁿ, R^o are independently selected from hydrogen, alkyl, haloalkyl, and alkoxy.

77b. In embodiment 77b, the compound of any one of embodiments 1 to 56, 59, 74, 75, 77, and 77a is wherein R^p is hydrogen, fluoro, or alkoxyalkyl.

78. In embodiment 78, the compound of any one of embodiments 1 to 56, 59, 74, 75, and 77, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-1-yl, or homomorpholin-1-yl, each ring substituted with Rⁿ, R^o, R^p, and R^q where Rⁿ and R^o are independently selected from hydrogen, deuterium, methyl, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyano, or methoxy, R^p is hydrogen, deuterium, methoxymethyl, or fluoro, and R^q is hydrogen, deuterium, or fluoro.

79. In embodiment 79, the compound of any one of embodiments 1 to 56, 59, 74, 75, 77, and 78, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form 3-methoxymethylazetidin-1-yl, 2-methoxymethyl-piperidin-1-yl, 3, 3, 4, 4-tetrafluoropyrrolidin-1-yl, morpholin-1-yl. 2, 6-dimethylmorpholin-4-yl, 2, 2- dimethylmorpholin-4-yl, 2- (trifluoromethyl) morpholin-4-yl, 2, 2-difluoromorpholin-4-yl, 2-methylmorpholin-4-yl, 3-methylmorpholin-4-yl, or 2- (difluoromethyl) morpholin-4-yl.

80. In embodiment 80, the compound of any one of embodiments 1 to 56, 59, 74, 75, and 77 to 79, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form morpholin-1-yl. 2, 6-dimethylmorpholin-4-yl, 2, 2-dimethylmorpholin-4-yl, 2- (trifluoromethyl) morpholin-4-yl, 2, 2-difluoromorpholin-4-yl, 2-methylmorpholin-4-yl, 3-methylmorpholin-4-yl, or 2- (difluoromethyl) morpholin-4-yl.

81. In embodiment 81, the compound of any one of embodiments 1 to 56, 59, 74, and 76, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form bicyclic heterocyclyl substituted with R^r, R^s, and R^t.

82. In embodiment 82, the compound of any one of embodiments 1 to 56, 59, 74, and 76, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form bridged heterocyclyl substituted with R^r, R^s, and R^t.

83. In embodiment 83, the compound of any one of embodiments 1 to 56, 59, 74, and 76, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form fused heterocyclyl substituted with R^r, R^s, and R^t.

84. In embodiment 84, the compound of any one of embodiments 1 to 56, 59, 74, and 76, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form spiroheterocyclyl substituted with R^r, R^s, and R^t.

84a In embodiment 84a, the compound of any one of embodiments 1 to 56, 59, 74, 76, and 81-84, or a pharmaceutically acceptable salt thereof, is wherein R^r, R^s, and R^t are independently selected from hydrogen, alkyl, halo, and alkoxy.

85. In embodiment 85, the compound of any one of embodiments 1 to 56, 59, 74, 76, and 81 to 84, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form a ring selected from:

wherein each ring is substituted with R^r, R^s, and R^t.

86. In embodiment 86, the compound of any one of embodiments 1 to 56, 59, 74, 76, and 81 to 85, or a pharmaceutically acceptable salt thereof, wherein R^t is hydrogen.

87. In embodiment 87, the compound of any one of embodiments 1 to 56, 59, 74, 76, and 81 to 86, or a pharmaceutically acceptable salt thereof, wherein R^s and R^t are hydrogen.

88. In embodiment 88, the compound of any one of embodiments 1 to 56, 59, 74, 76, and 81 to 87, or a pharmaceutically acceptable salt thereof, wherein R^r, and R^s and R^t (where applicable) are independently selected from hydrogen, methyl, methoxy, or fluoro.

89. In embodiment 89, the compound of any one of embodiments 1 to 55, 57, 58, and 60, or a pharmaceutically acceptable salt thereof, wherein R³⁹ is hydrogen, deuterium, alkyl, deuterioalkyl, haloalkyl, haloalkoxyalkyl, or alkoxyalkyl and R⁴⁰ is hydrogen, alkyl, deuterioalkyl, cycloalkyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, or heterocyclyl optionally substituted with one or two substituents independently selected from alkyl, halo, and haloalkyl.

90. In embodiment 90, the compound of any one of embodiments 1 to 55, 57, 58, 60, and 89, or a pharmaceutically acceptable salt thereof, wherein R³⁹ is hydrogen or deuterium and R⁴⁰ is hydrogen, alkyl, deuterioalkyl, cycloalkyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, or heterocyclyl optionally substituted with one or two substituents independently selected from alkyl, halo, and haloalkyl.

91. In embodiment 91, the compound of any one of embodiments 1 to 55, 57, 58, 60, and 89, or a pharmaceutically acceptable salt thereof, wherein R³⁹ is alkyl.

92. In embodiment 92, the compound of any one of embodiments 1 to 55, 57, 58, 60, and 89, or a pharmaceutically acceptable salt thereof, wherein R³⁹ is haloalkyl

93. In embodiment 93, the compound of any one of embodiments 1 to 55, 57, 58, 60, and 89, or a pharmaceutically acceptable salt thereof, wherein R³⁹ is haloalkoxyalkyl.

94. In embodiment 94, the compound of any one of embodiments 1 to 55, 57, 58, 60, and 89, or a pharmaceutically acceptable salt thereof, wherein R³⁹ is alkoxyalkyl.

95. In embodiment 95, the compound of any one of embodiments 1 to 55, 57, 58, 60, and 89, or a pharmaceutically acceptable salt thereof, wherein R³⁹ is deuterioalkyl.

96. In embodiment 96, the compound of any one of embodiments 1 to 55, 57, 58, 60, and 89 to 95, or a pharmaceutically acceptable salt thereof, wherein R⁴⁰ is alkoxy.

97. In embodiment 97, the compound of any one of embodiments 1 to 55, 57, 58, 60, and 89 to 95, or a pharmaceutically acceptable salt thereof, wherein R⁴⁰ is alkoxyalkyl.

98. In embodiment 98, the compound of any one of embodiments 1 to 55, 57, 58, 60, and 89 to 95, or a pharmaceutically acceptable salt thereof, wherein R⁴⁰ is haloalkyl.

99. In embodiment 99, the compound of any one of embodiments 1 to 55, 57, 58, 60, and 89 to 95, or a pharmaceutically acceptable salt thereof, wherein R⁴⁰ is haloalkoxyalkyl.

100. In embodiment 100, the compound of any one of embodiments 1 to 55, 57, 58, 60, and 89 to 95, or a pharmaceutically acceptable salt thereof, wherein R⁴⁰ is cycloalkyl.

101. In embodiment 101, the compound of any one of embodiments 1 to 55, 57, 58, 60, and 89 to 95, or a pharmaceutically acceptable salt thereof, wherein R⁴⁰ is deuterioalkyl.

102. In embodiment 102, the compound of any one of embodiments 1 to 55, 57, 58, 60, and 89 to 95, or a pharmaceutically acceptable salt thereof, wherein R⁴⁰ is heterocyclyl optionally substituted with one or two substituents independently selected from alkyl, halo, and haloalkyl.

103. In embodiment 103, the compound of any one of embodiments 1 to 55, 57, 58, and 60, or a pharmaceutically acceptable salt thereof, wherein R³⁹ is hydrogen, methyl, methyl-d3, methoxyethyl, ethoxyethyl, or propoxyethyl; and R⁴⁰ is hydrogen, methyl, methyl-D3. cyclopropyl, 2, 2-difluoroethyl, 2, 2, 2-trifluoroethyl, 2, 2-difluoroethoxy, 2, 2, 2-trifluoroethoxy, methoxyethyl, ethoxyethyl, oxetan-3-yl, tetrahydrofuranyl, or tetrahydropyranyl.

104. In embodiment 104, the compound of any one of embodiments 1 to 55, 57, 58, and 60, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl wherein (a) heterocyclyl is substituted R^u, R^v, R^w, and R^x and (b) bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiroheterocyclyl are independently substituted with R^y, R^y1, and R^y2.

105. In embodiment 105, the compound of any one of embodiments 1 to 56, 59, and 104, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form heterocyclyl substituted with R^u, R^v, R^w, and R^x.

106. In embodiment 106, the compound of any one of embodiments 1 to 56, 57, 58, 60, and 104, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, each ring independently substituted with R^y, R^y1, and R^y2.

107. In embodiment 107, the compound of any one of embodiments 1 to 56, 57, 58, 60, 104, and 105, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-1-yl, or homomorpholin-1-yl, each ring substituted with R^u, R^v, R^w, and R^x.

108. In embodiment 108, the compound of any one of embodiments 1 to 56, 57, 58, 60, 104, 105, and 107, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-1-yl, or homomorpholin-1-yl, each ring substituted with R^u, R^v, R^w, and R^x where R^u and R^v are independently selected from hydrogen, deuterium, methyl, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyano, or methoxy, R^w is hydrogen, deuterium, or fluoro, and R^x is hydrogen, deuterium, or fluoro.

109. In embodiment 109, the compound of any one of embodiments 1 to 56, 57, 58, 60, 104, 105, 107, and 108, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form 3-methoxymethylazetidin-1-yl, 2-methoxymethyl-piperidin-1-yl, 3, 3, 4, 4-tetrafluoropyrrolidin-1-yl, morpholin-1-yl. 2, 6- dimethylmorpholin-4-yl, 2, 2-dimethylmorpholin-4-yl, 2- (trifluoromethyl) morpholin-4-yl, 2, 2-difluoromorpholin-4-yl, 2-methylmorpholin-4-yl, 3-methylmorpholin-4-yl, or 2- (difluoromethyl) morpholin-4-yl.

110. In embodiment 110, the compound of any one of embodiments 1 to 56, 57, 58, 60, 104, 105, and 107 to 109, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form morpholin-1-yl. 2, 6-dimethylmorpholin-4-yl, 2, 2-dimethylmorpholin-4-yl, 2- (trifluoromethyl) morpholin-4-yl, 2, 2-difluoromorpholin-4-yl, 2-methylmorpholin-4-yl, 3-methylmorpholin-4-yl, or 2- (difluoromethyl) morpholin-4-yl.

111. In embodiment 111, the compound of any one of embodiments 1 to 56, 57, 58, 60, 104, and 106, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form bicyclic heterocyclyl substituted with R^y, R^y1, and R^y2.

112. In embodiment 112, the compound of any one of embodiments 1 to 56, 57, 58, 60, 104, and 106, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form bridged heterocyclyl substituted with R^y, R^y1, and R^y2.

113. In embodiment 113, the compound of any one of embodiments 1 to 56, 57, 58, 60, 104, and 106, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form fused heterocyclyl substituted with R^y, R^y1, and R^y2.

114. In embodiment 114, the compound of any one of embodiments 1 to 56, 57, 58, 60, 104, and 106, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form spiroheterocyclyl substituted with R^y, R^y1, and R^y2.

115. In embodiment 115, the compound of any one of embodiments 1 to 56, 57, 58, 60, 104, 106, and 111 to 114, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form a ring selected from:

wherein each ring is substituted with R^r, R^s, and R^t.

116. In embodiment 116, the compound of any one of embodiments 1 to 58, 60, 104, 106, and 111 to 115, or a pharmaceutically acceptable salt thereof, wherein R^y2 is hydrogen.

117. In embodiment 117, the compound of any one of embodiments 1 to 58, 60, 104, 106, and 111 to 116, or a pharmaceutically acceptable salt thereof, wherein R^y1 and R^y2 are hydrogen.

118. In embodiment 118, the compound of any one of embodiments 1 to 58, 60, 104, 106, and 111 to 117, or a pharmaceutically acceptable salt thereof, wherein R^y, and R^y1 and R^y2 (where applicable) are independently selected from hydrogen, methyl, methoxy, or fluoro.

118a. In embodiment 118a, the compound of any one of embodiments 1 to 55, or a pharmaceutically acceptable salt thereof, is wherein R^b, R^e, and R^h are independently – (Q²) -OR⁴¹.

118a1. In embodiment 118a1, the compound of any one of embodiments 1 to 55 and 118a, or a pharmaceutically acceptable salt thereof, is wherein Q² is alkylene.

118a2. In embodiment 118a2, the compound of any one of embodiments 1 to 55, 118a, and 118a1, or a pharmaceutically acceptable salt thereof, is wherein Q² is deuterioalkylene.

118a3. In embodiment 118a3, the compound of any one of embodiments 1 to 55 and 118a to 118a2, or a pharmaceutically acceptable salt thereof, is wherein Q² is methylene, methylene-d2, ethylene, propylene, or butylene.

118a4. In embodiment 118a4, the compound of any one of embodiments 1 to 55 and 118a to 118a3, or a pharmaceutically acceptable salt thereof, is wherein Q² is methylene, methylene-d2, ethylene, or propylene.

118a5. In embodiment 118a5, the compound of any one of embodiments 1 to 55 and 118a to 118a4, or a pharmaceutically acceptable salt thereof, is wherein R⁴¹ is cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) substituted with R^y3, R^y4, and R^y5 independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, and nitrile.

118a6. In embodiment 118a6, the compound of any one of embodiments 1 to 55 and 118a to 118a4, or a pharmaceutically acceptable salt thereof, is wherein R⁴¹ is cycloalkylalkyl (such as cyclopropylmethyl or -ethyl, cyclobutylmethyl or -ethyl, cyclopentylmethyl or -ethyl or cyclohexylmethyl or -ethyl) substituted with R^y3, R^y4, and R^y5 independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, and nitrile.

118a7. In embodiment 118a7, the compound of any one of embodiments 1 to 55 and 118a to 118a4, or a pharmaceutically acceptable salt thereof, is wherein R⁴¹ is haloalkoxyalkyl such as trifluoromethoxymethyl or difluoromethoxymethyl.

118a8. In embodiment 118a8, the compound of any one of embodiments 1 to 55 and 118a to 118a4, or a pharmaceutically acceptable salt thereof, is wherein R⁴¹ is heterocyclyl (such as pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl) substituted with R^y3, R^y4, and R^y5 independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, and nitrile.

118a9. In embodiment 118a9, the compound of any one of embodiments 1 to 55 and 118a to 118a4, or a pharmaceutically acceptable salt thereof, is wherein R⁴¹ is heterocyclylalkyl (such as pyrrolidinylmethyl or -ethyl, piperidinylmethyl or -ethyl, piperazinylmethyl or -ethyl or morpholinylmethyl or -ethyl) substituted with R^y3, R^y4, and R^y5 independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, and nitrile.

118a10. In embodiment 118a10, the compound of any one of embodiments 1 to 55 and 118a to 118a4, or a pharmaceutically acceptable salt thereof, is wherein R⁴¹ is phenyl substituted with R^y3, R^y4, and R^y5 independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, and nitrile.

118a11. In embodiment 118a11, the compound of any one of embodiments 1 to 55 and 118a to 118a4, or a pharmaceutically acceptable salt thereof, is wherein R⁴¹ is phenylmethyl or -ethyl substituted with R^y3, R^y4, and R^y5 independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, and nitrile.

118a12. In embodiment 118a12, the compound of any one of embodiments 1 to 55 and 118a to 118a4, or a pharmaceutically acceptable salt thereof, is wherein R⁴¹ is heteroaryl (such as furanyl, pyridyl, pyrazinyl, quinolinyl, or isoquinolinyl) substituted with R^y3, R^y4, and R^y5 independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, and nitrile.

118a13. In embodiment 118a13, the compound of any one of embodiments 1 to 55 and 118a to 118a4, or a pharmaceutically acceptable salt thereof, is wherein R⁴¹ is heteroaryalkyl (such as furanylmethyl or -ethyl, pyridylmethyl or -ethyl, pyrazinylmethyl or -ethyl, quinolinylmethyl or -ethyl, or isoquinolinylmethyl or -ethyl) substituted with R^y3, R^y4, and R^y5 independently selected from hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, and nitrile.

119. In embodiment 119, the compound of any one of embodiments 1 to 118a13, or a pharmaceutically acceptable salt thereof, is wherein R^c, R^f, and Rⁱ are independently hydrogen, deuterium, methyl, ethyl, methoxy, ethoxy, methyloxy, ethyloxy, chloro, or fluoro.

120. In embodiment 120, the compound of any one of embodiments 1 to 119, or a pharmaceutically acceptable salt thereof, is wherein R^c, R^f, and Rⁱ are hydrogen.

121. In embodiment 121, the compound of any one of embodiments 1 to 119, or a pharmaceutically acceptable salt thereof, is wherein R^c, R^f, and Rⁱ are deuerium.

122. In embodiment 122, the compound of any one of embodiments 1 to 119, or a pharmaceutically acceptable salt thereof, is wherein R^c, R^f, and Rⁱ are independently methyl, methoxy, methyloxy, chloro, or fluoro.

123. In embodiment 123, the compound of any one of embodiments 1 to 122, or a pharmaceutically acceptable salt thereof, is wherein R^c1, R^f1, and Rⁱ¹ are independently selected from hydrogen, deuterium, or fluoro.

124. In embodiment 124, the compound of any one of embodiments 1 to 123, or a pharmaceutically acceptable salt thereof, is wherein R^c1, R^f1, and Rⁱ¹ are hydrogen.

125. In embodiment 125, the compound of any one of embodiments 1 to 123, or a pharmaceutically acceptable salt thereof, is wherein R^c1, R^f1, and Rⁱ¹ are deuterium.

126. In embodiment 126, the compound of any one of embodiments 1 to 123, or a pharmaceutically acceptable salt thereof, is wherein R^c1, R^f1, and Rⁱ¹ are fluoro.

127. In embodiment 127, the compound of any one of embodiments 1 to 126, or a pharmaceutically acceptable salt thereof, is wherein Z is O.

128. In embodiment 128, the compound of any one of embodiments 1 to 127, or a pharmaceutically acceptable salt thereof, is wherein:

R¹ is a ring of formulawhere one of m and n is 0, 1, or 2, and the other of m and n is 0, 1, 2, or 3.

128a1. In embodiment 128a1, the compound of any one of embodiments 1 to 128, or a pharmaceutically acceptable salt thereof, is wherein m and n are each 1, or one of m and n is 1 and the other of m and n is 2.

128b1. In embodiment 128b1, the compound of any one of embodiments 1 to 128, or a pharmaceutically acceptable salt thereof, is wherein m and n are each 1, or one of m and n is 1.

128c1. In embodiment 128c1, the compound of any one of embodiments 1 to 128, or a pharmaceutically acceptable salt thereof, is wherein one of m and n is 1 and the other of m and n is 2.

128d1. In embodiment 128d1, the compound of any one of embodiments 1 to 128, or a pharmaceutically acceptable salt thereof, is wherein m and n are each 1.

128e1. In embodiment 128e1, the compound of any one of embodiments 1 to 128, or a pharmaceutically acceptable salt thereof, is wherein m is 1 and n is 3.

128f1. In embodiment 128f1, the compound of any one of embodiments 1 to 128e1, or a pharmaceutically acceptable salt thereof, is wherein R⁶ and R⁷ are independently selected from hydrogen, methyl, and ethyl, and R^6a and R^6b are hydrogen.

128g1. In embodiment 128g1, the compound of any one of embodiments 1 to 128e1, or a pharmaceutically acceptable salt thereof, is wherein R⁶ is cyanomethyl and R⁷ is hydrogen, methyl, or ethyl, preferably R⁷ is hydrogen, and R^6a and R^6b are hydrogen.

128h1. In embodiment 128h1, the compound of any one of embodiments 1 to 128e1, or a pharmaceutically acceptable salt thereof, is wherein R⁶ and R⁷ are attached to the carbon atoms of the ring that are opposite or diagonal to each other and combine to form – (CH₂) _z-where z is 1, 2, or 3, preferably z is 2, and R^6a and R^6b are hydrogen.

128i1. In embodiment 128i1, the compound of any one of embodiments 1 to 128e1, or a pharmaceutically acceptable salt thereof, is wherein R⁶ and R⁷ are attached to the carbon atoms of the ring that are opposite or diagonal to each other and combine to form – (CH₂) _z-where z is 1, 2, or 3, preferably 2, R^6b is hydrogen and R^6a is attached to a carbon of the – (CH₂) _z-group and is alkylidenyl, preferably =CH₂.

128j1. In embodiment 128j1, the compound of any one of embodiments 1 to 128, 128d1 and 128h1, or a pharmaceutically acceptable salt thereof, is wherein R¹ is:

129. In embodiment 129, the compound of any one of embodiments 1 to 127, or a pharmaceutically acceptable salt thereof, is wherein R¹ is a ring of formula

130. In embodiment 130, the compound of any one of embodiments 1 to 127, or a pharmaceutically acceptable salt thereof, is wherein R¹ is a ring of formula

131a1. In embodiment 131a1, the compound of any one of embodiments 1 to 127 and 130, or a pharmaceutically acceptable salt thereof, is wherein R¹ is:

132. In embodiment 132, the compound of any one of embodiments 1 to 127, and 129, or a pharmaceutically acceptable salt thereof, is wherein R¹ is a ring of formula:

133. In embodiment 133, the compound of any one of embodiments 1 to 127, or a pharmaceutically acceptable salt thereof, is wherein R¹ is a ring of formulaIn a subembodiment, R^29a and R^29b are hydrogen.

134. In embodiment 134, the compound of Formula (I) of any one of embodiments 1 to 133, or a pharmaceutically acceptable salt thereof, has a structure of formula (I’a) as follows:

135. In embodiment 135, the compound of Formula (I) of any one of embodiments 1 to 133, or a pharmaceutically acceptable salt thereof, has a structure of formula (I’b) as follows:

136. In embodiment 136, the compound of Formula (I) of any one of embodiments 1 to 133, or a pharmaceutically acceptable salt thereof, has a structure of formula (I’c) as follows:

137. In embodiment 137, the compound of Formula (I) of any one of embodiments 1 to 133 and 136, or a pharmaceutically acceptable salt thereof, has a structure of formula (I’d) as follows:

138. In embodiment 138, the compound of Formula (I) of any one of embodiments 1 to 133, or a pharmaceutically acceptable salt thereof, has a structure of formula (I’e) as follows:

139. In embodiment 139, the compound of Formula (I) of any one of embodiments 1 to 133, and 138, or a pharmaceutically acceptable salt thereof, has a structure of formula (I’f) as follows:

140. In embodiment 140, the compound of any one of embodiments 1 to 139, or a pharmaceutically acceptable salt thereof, is wherein R⁵ is -Q-R³⁷ where Q is a bond and R³⁷ is cycloalkyl, fused cycloalkyl, fused spirocycloalkyl, aryl, heteroaryl, or fused heteroaryl, wherein aryl, heteroaryl, and fused heteroaryl are substituted with R^aa, R^bb, R^cc and R^dd wherein R^aa and R^bb are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R^cc is hydrogen, alkenyl, alkynyl, cyanoalkenyl, cyanoalkynyl, or halo, and R^dd is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, alkylthio, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.

141. In embodiment 141, the compound of any one of embodiments 1 to 139, or a pharmaceutically acceptable salt thereof, is wherein R⁵ is -Q-R³⁷ where Q is alkylene and R²⁷is cycloalkyl, aryl, or fused heteroaryl, wherein aryl, fused heteroaryl, and heteroaryl are substituted with R^aa, R^bb, R^cc and R^dd wherein R^aa and R^bb are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R^cc is hydrogen, alkynyl, or halo, and R^dd is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.

142. In embodiment 142, the compound of any one of embodiments 1 to 139, or a pharmaceutically acceptable salt thereof, is wherein R⁵ is -Q-R³⁷ where Q is -C (O) -and R³⁷ is cycloalkyl, aryl, fused heteroaryl, or heteroaryl, wherein aryl, fused heteroaryl and heteroaryl are substituted with R^aa, R^bb, R^cc and R^dd wherein R^aa and R^bb are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R^cc is hydrogen, alkynyl, or halo, and R^dd is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.

143. In embodiment 143, the compound of any one of embodiments 1 to 139, or a pharmaceutically acceptable salt thereof, is wherein R³⁷ is cycloalkyl, fused cycloalkyl, aryl, or heteroaryl wherein aryl, and heteroaryl are substituted with R^aa, R^bb, R^cc and R^dd wherein R^aa and R^bb are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R^cc is hydrogen, alkenyl, alkynyl, cyanoalkenyl, cyanoalkynyl, or halo, and R^dd is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.

144. In embodiment 144, the compound of any one of embodiments 1 to 139, or a pharmaceutically acceptable salt thereof, is wherein R⁵ is -Q-R³⁷ where Q is a bond and R³⁷ is phenyl or naphthyl substituted with R^aa, R^bb, R^cc and R^dd.

145. In embodiment 99, the compound of any one of embodiments 1 to 139 and 144, or a pharmaceutically acceptable salt thereof, is wherein R⁵ is -Q-R³⁷ where Q is a bond and R³⁷ is phenyl or naphthyl substituted with R^aa, R^bb, R^cc and R^dd where R^aa and R^bb are independently selected from hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cycloalkyl, amino, cyano, and hydroxyalkyl, R^cc is hydrogen, fluoro, alkynyl, and R^dd is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.

146. In embodiment 146, the compound of any one of embodiments 1 to 145, or a pharmaceutically acceptable salt thereof, is wherein R^aa and R^bb independently selected from hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, difluoromethyl, trifluoromethoxy, hydroxy, methyl, ethoxy, cyclopropyl, amino, cyano, and hydroxymethyl, R^cc is hydrogen, ethynyl, 2-cyanovinyl, 2-cyanoethyn-1-yl, or fluoro, and R^dd is hydrogen, methyl, fluoro, amino, or cyclopropyl.

147. In embodiment 147, the compound of any one of embodiments 1 to 139, or a pharmaceutically acceptable salt thereof, is wherein R⁵ is -Q-R³⁷ where Q is a bond and R³⁷ is heteroaryl or fused heteroaryl substituted with R^aa, R^bb, R^cc and R^dd.

148. In embodiment 148, the compound of any one of embodiments 1 to 139 and 147, or a pharmaceutically acceptable salt thereof, is wherein R⁵ is -Q-R³⁷ where Q is a bond and R³⁷ is a monocyclic heteroaryl (e.g., pyridyl, pyrimidinyl, benzothiazolyl, pyrazolyl) substituted with R^aa, R^bb, R^cc and R^dd.

149. In embodiment 149, the compound of any one of embodiments 1 to 139 and 147, or a pharmaceutically acceptable salt thereof, is wherein R⁵ is -Q-R³⁷ where Q is a bond and R³⁷ is bicyclic heteroaryl (e, g, quinolinyl, isoquinolinyl, or indazolyl) , substituted with R^aa, R^bb, R^cc and R^dd.

150. In embodiment 150, the compound of any one of embodiments 1 to 139 and 147 to 149, or a pharmaceutically acceptable salt thereof, is wherein the heteroaryl is substituted with R^aa, R^bb, and R^dd where R^aa and R^bb independently selected from hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cycloalkyl, amino, cyano, and hydroxyalkyl and R^dd is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.

151. In embodiment 151, the compound of any one of embodiments 1 to 139 and 147 to 150, or a pharmaceutically acceptable salt thereof, is wherein R^aa and R^bb are independently selected from hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, difluoromethyl, trifluoromethoxy, hydroxy, methyl, ethoxy, cyclopropyl, amino, cyano, and hydroxymethyl, R^cc is hydrogen or fluoro, and R^dd is hydrogen, methyl, fluoro, amino, or cyclopropyl.

152. In embodiment 152, the compound of any one of embodiments 1 to 151, or a pharmaceutically acceptable salt thereof, is wherein R⁵ is -Q-R³⁷ where Q is a bond and R³⁷ is:

153. In embodiment 153, the compound of any one of embodiments 1 to 139, 144 to 146, and 152, or a pharmaceutically acceptable salt thereof, is wherein R⁵ is -Q-R³⁷ where Q is a bond and R³⁷ is:

154. In embodiment 154, the compound of any one of embodiments 1 to 139, 144 to 146, and 153, or a pharmaceutically acceptable salt thereof, is wherein R⁵ is -Q-R³⁷ where Q is a bond and R⁴⁴ is:

.

154a. In embodiment 154a, the compound of any one of embodiments 1 to 139, 144 to 146, and 153, or a pharmaceutically acceptable salt thereof, is wherein R⁵ is -Q-R³⁷ where Q is a bond and R⁴⁴ is:

155. In embodiment 155, the compound of any one of embodiments 1 to 154a, or a pharmaceutically acceptable salt thereof, is wherein R² is hydrogen, halo, or alkyl, and R³ is hydrogen, halo, cycloalkyloxy, or alkyl.

156. In embodiment 156, the compound of any one of embodiments 1 to 155a, or a pharmaceutically acceptable salt thereof, is wherein R² and R³ are each hydrogen.

157. In embodiment 157, the compound of any one of embodiments 1 to 155a, or a pharmaceutically acceptable salt thereof, is wherein R² is hydrogen or chloro and R³ is hydrogen, fluoro, or cyclopropyloxy.

158. In embodiment 158, the compound of any one of embodiments 1 to 155a, or a pharmaceutically acceptable salt thereof, is wherein R² is hydrogen and R³ is fluoro.

General Synthetic Scheme

Compounds Formula (I) can be made by the methods depicted in the reaction schemes shown below.

The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis. ) , Bachem (Torrance, Calif. ) , or Sigma (St. Louis, Mo. ) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991) ; Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989) ; Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991) , March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989) . These schemes are merely illustrative of some methods by which the compounds Formula (I) can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art reading this disclosure. The starting materials and the intermediates, and the final products of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range from about –78 ℃ to about 150 ℃, such as from about 0 ℃ to about 125 ℃ and further such as at about room (or ambient) temperature, e.g., about 20 ℃.

Compounds of Formula (I) can be prepared by methods known in the art. For example, compound of Formula (I) where R¹ is a ring of formula (a’) where R^6a and R^6b are hydrogen, respectively, R⁴ is -O-R³⁷, and other groups are as defined in the Summary can be prepared as illustrated and described in Scheme 1 below.

Scheme 1

Chlorination of a compound of formula 1-a where X^a is a halogen, and other groups as defined in the Summary or a precursor group thereof (a precursor group as used herein is one that can be converted to a group covered by Formula (I) . A representative example of conversion of a precursor group to a group covered by Formula (I) is illustrated and described in Scheme 3 below) with a suitable chlorination reagent such as POCl₃ optionally in presence of a base such as DIPEA provides a 2, 4-dichloro compound of formula 1-b. Compounds of formula 1-a is either commercially available or they can be prepared by method well known in the art. Once such method is illustrated and described in Methods 1 and 2 below.

Treatment of compound 1-b with an amine of formula (a”) where m, n, R⁶ and R⁷ are as defined in the Summary or a precursor group thereof and PG is a suitable amino protecting group such as Boc, CBz, and the like, in the presence of a base such as DEA or DBU and the like, provides a 2-chloro compound of formula 1-c. Displacement of chloro group at C-2 position in compound 1-c with an alcohol of formula 1-f where R^30A-Q^1-OPG¹ is a precursor group of R³⁰, provides a compound of formula 1-d. Alcohols of formula 1-f are either commercially available or can be made by methods known in the art. Representative methods for preparing compound of formula 1-f are described in in the Working Examples below.

Amines of formula (a”) are either commercially available or can be made by methods known in the art. For example, benzyl 2- (cyanomethyl) piperazine-1-carboxylate, tert-butyl 2- (cyanomethyl) piperazine-1-carboxylate, benzyl 2, 5-dimethylpiperazine-1-carboxylate, tert-butyl 2-methylpiperazine-1-carboxylate, tert-butyl piperazine-1-carboxylate, benzyl piperazine-1-carboxylate are commercially available. Others can be prepared by methods well known in the art.

Reaction of a compound of formula 1-d with a suitable organometallic reagent of formula R⁵-M where R⁵ is cycloalkyl, aryl or heteroaryl as defined in the Summary and M is boronic acid, boronic ester, or stannane, under Suzuki, Negeshi, and Stille reaction conditions, followed by removal of hydroxy protecting group and reaction of the resulting hydroxy group with an amine of formula NHR³⁹R⁴⁰ under carbomoylation reaction conditions provides a compound of formula 1-e.

Removal of amino protecting group PG in 1-e under standard reaction condition provides a compound of Formula (I) . It will be apparent to a person of ordinary skilled in the art, that compounds of Formula (I) where R¹ is a group of formula (b’) , (f’) or (g’) can be similarly prepared by using appropriate mono-protected amines. For example, compound of Formula (I) where R¹ is a ring of formula (b’) can be prepared using tert-butyl 2, 7-diazaspiro [3.5] nonane-2-carboxylate, and tert-butyl 2, 6-diazaspiro [3.4] octane-2-carboxylate. Other mono-protected amines can be prepared by methods disclosed in the art, e.g., PCT application publication No. WO2019099524.

Compounds of formula 1-a can be prepared by methods well known in the art. For example,

1. Compounds of Formula 1-a where X^a is halogen, U is CH, V is N, W is CH, R² and R³ are as defined in the Summary (or any embodiments thereof) can be prepared as illustrated and described below.

Iodination of a compound of formula 1 where X^a is a halo and R² and R³ are as defined in the Summary, with NIS and a suitable acid such as TsOH provides a compound of formula 2. The iodine in 2 can be converted to ethyl carboxylate under carbonylation condition including Pd catalyst such as Pd (PPh₃) ₄ in carbon monoxide atmosphere and ethanol solvent to provide a compound of formula 3. Compound 3 can react with triphosgene to provide trichloroacetamido compound of formula 4, which upon treatment with ammonia in an organic solvent such as methanol, undergoes cyclization to provide compound of formula 1-a. Compounds of formula 1 are either commercially available or can be made by methods known in the art. For example, 2-chloro-3-fluoropyridin-4-amine and 2-chloropyridin-4-amine are commercially available.

2. Compounds of Formula 1-a where X^a is halogen, U, V and W are CH, R² and R³ are as defined in the Summary (or any embodiments thereof) can be prepared by reacting a compound of formulawith urea at elevated temperature. Compounds of formula 5 are either commercially available or can be made by methods known in the art. For example, 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid, 2-amino-4-bromo-3-fluorobenzoic acid and 2-amino-4-bromobenzoic acid are commercially available.

Alternatively, compounds of Formula (I) where R¹ is, for example, a ring of formula (a’) , R⁴ is -O-R³⁰, and other groups are as defined in the Summary can be prepared as illustrated and described in Scheme 2 below.

Scheme 2

Coupling reaction between compound 1-a and a suitable organometallic reagent of formula R⁵-M where R⁵ is cycloalkyl, aryl or heteroaryl as defined in the Summary or a precursor group thereof and M is boronic acid, boronic ester, or stannane, under Suzuki, Negeshi, and Stille reaction conditions respectively, to provide a compound of formula 2-a. Chlorination of a compound of formula 2-a with a suitable chlorination reagent such as POCl₃ optionally in presence of a base such as DIPEA provides compound of formula 2-b. Compound 2-b is converted to a compound of Formula (I) as described in Scheme 1 above.

Compounds of Formula (I) where R⁴ iscan be prepared by a precursor group of formulaas illustrated and described in Scheme 3 below

Scheme 3

Removal of the hydroxy protecting group in formula 3-a provides a compound of formula 3-b. Treatment of a compound of formula 3-b with a couling agent such as CDI, (4-nitrophenyl) carbonochloridate and the like, followed by treatment of the resulting intermediate with an amine of formula HR³⁹R⁴⁰, where R³⁹ and R⁴⁰ are as defined in the Summary provides a compound of formula 3-c which can the converted to compound of Formula (I) as described above.

Utility

The present disclosure provides treatment of cancer mediated by K-ras, in particular with K-ras G12D mutants. In some embodiments, the cancer is pancreatic cancer, colorectal cancer, lung cancer, gall bladder cancer, thyroid cancer, and bile duct cancer. In certain embodiments the lung cancer is a non-small cell lung carcinoma (NSCLC) , for example adenocarcinoma, squamous-cell lung carcinoma or large-cell lung carcinoma. In some embodiments, the lung cancer is a small cell lung carcinoma. Other lung cancers treatable with the disclosed compounds include, but are not limited to, glandular tumors, carcinoid tumors and undifferentiated carcinomas.

K-ras G12D mutations are observed in hematological malignancies that affect blood, bone marrow, and/or lymph nodes. As such the compounds of Formula (I) or a pharmaceutically acceptable salt thereof can be used for the treatment of acute lymphoblastic leukemia (ALL) , acute myelogenous leukemia (AML) , chronic lymphocytic leukemia (CLL) , small lymphocytic lymphoma (SLL) , chronic myelogenous leukemia (CML) , acute monocytic leukemia (AMoL) and/or other leukemias, lymphomas such as all subtypes of Hodgkins lymphoma or non-Hodgkins lymphoma, plasma cell malignancies such as multiple myeloma, mantle cell lymphoma, and Waldenstrom’s macroglubunemia.

The compounds of Formula (I) , or a pharmaceutically acceptable salt thereof can be used for the treatment of a hyperproliferative disorder or metastasis in human who suffers from a cancer such as acute myeloid leukemia, cancer in adolescents, adrenocortical carcinoma childhood, AIDS related cancers (e.g. Lymphoma and Kaposi's Sarcoma) , anal cancer, appendix cancer, astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervical cancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL) , chronic myelogenous leukemia (CML) , chronic myleoproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS) , embryonal tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST) , germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS) , lung cancer, lymphoma, metastatic squamous neck cancer with occult primary, midline tract carcinoma, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma/plasma cell neoplasm, mycosis fungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms, multiple myeloma, merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-hodgkin lymphoma, non-small cell lung cancer (NSCLC) , oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach (gastric) cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter, trophoblastic tumor, unusual cancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or viral-induced cancer. The compounds of Formula (I) , or a pharmaceutically acceptable salt thereof can also be used for the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis) , restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH) ) .

Testing

The K-Ras G12D activity of the compounds of Formula (I) , or a pharmaceutically acceptable salt thereof can be tested using the in vitro assay described in Biological Examples 1 below.

Pharmaceutical Compositions

In general, the compounds Formula (I) (unless stated otherwise, reference to compound/compounds of Formula (I) herein includes any embodiments thereof described herein or a pharmaceutically acceptable salt thereof) will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Therapeutically effective amounts of compounds Formula (I) may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. A suitable dosage level may be from about 0.1 to about 250 mg/kg per day; about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per day. Within this range the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day. For oral administration, the compositions can be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient. The actual amount of the compound Formula (I) , i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound being utilized, the route and form of administration, and other factors.

In general, compounds Formula (I) will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository) , or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.

The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules, including enteric coated or delayed release tablets, pills or capsules are preferred) and the bioavailability of the drug substance.

The compositions are comprised of in general, a compound of Formula (I) in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are generally non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula (I) . Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.

Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

The compounds of Formula (I) may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

In addition to the formulations described previously, the compounds of Formula (I) may also be formulated as a depot preparation. Such long -acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

The compounds of Formula (I) may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

Certain compounds of Formula (I) may be administered topically, that is by non-systemic administration. This includes the application of a compound of Formula (I) externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient for topical administration may comprise, for example, from 0.001%to 10%w/w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10%w/w. In other embodiments, it may comprise less than 5%w/w. In certain embodiments, the active ingredient may comprise from 2%w/w to 5%w/w. In other embodiments, it may comprise from 0.1%to 1%w/w of the formulation.

For administration by inhalation, compounds of Formula (I) may be conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds of Formula (I) may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator. Other suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 20th ed., 2000) .

The level of the compound of Formula (I) in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt. %) basis, from about 0.01-99.99 wt. %of a compound of Formula (I) based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. For example, the compound is present at a level of about 1-80 wt. %.

Combinations and Combination Therapies

The compounds of Formula (I) or a pharmaceutically acceptable salt thereof may be used in combination with one or more other drugs in the treatment of diseases or conditions for which compounds of Formula (I) or the other drugs may have utility. Such other drug (s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of Formula (I) or a pharmaceutically acceptable salt thereof. When a compound of Formula (I) or a pharmaceutically acceptable salt thereof is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula (I) or a pharmaceutically acceptable salt thereof can be used. Accordingly, the pharmaceutical compositions of the present disclosure also include those that contain one or more other drugs, in addition to a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The combination therapy may also include therapies in which the compound of Formula (I) or a pharmaceutically acceptable salt thereof and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of Formula (I) and the other active ingredients may be used in lower doses than when each is used singly. The weight ratio of the compound of this disclosure to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.

Where the subject in need is suffering from or at risk of suffering from cancer, the patient can be treated with a compound of Formula (I) or a pharmaceutically acceptable salt thereof in any combination with one or more other anti-cancer agents including but not limited to:

MAP kinase pathway (RAS/RAF/MEK/ERK) inhibitors including but not limited to: Vemurafanib (PLX4032, CAS No. 918504-65-1) , Dabrafenib (CAS No. 1195765-45-7) , Encorafenib (LGX818 CAS No. 1269440-17-6) , TQ-B3233, XL-518 (Cas No. 1029872-29-4, available from ACC Corp) ; trametinib (CAS No. 871700-17-3) , selumetinib (AZD6244 CAS No. 606143-52-6) , TQ-B3234, PD184352 (CAS No. 212631-79-3) , PD325901 (CAS No. 391210-10-9) , TAK-733 (CAS No. 1035555-63-5) , pimasertinib (CAS No. 1236699-92-5) , binimetinib (CAS No. 606143-89-9) , refametinib (CAS No. 923032-37-5) , cobimetinib (GDC-0973 CAS No. 934660-93-2) , AZD8330 (CAS No. 869357-68-6) , BVD-523 (CAS No. 869886-67-9) , LTT462 (CAS No. 869886-67-9) , , AMG510 (CAS No. 2296729-00-3) , ARS853 (CAS No. 1629268-00-3) , and any RAS inhibitors disclosed in patents WO2016049565, W020l6l64675, W020l6l68540, WO2017015562, WO2017058728, WO2017058768, WO2017058792, W020l7058805, W02017058807, W02017058902, WO2017058915, W02017070256, WO2017087528, W02017100546, WO2017172979, W02017201161, WO2018064510, WO2018068017, and WO2018119183;

SHP2 inhibitors including but not limited to: SHP099 (CAS No. 2200214-93-1) , TNO155 (CAS No. 1801765-04-7) , RMC4630, JAB-3312, JAB-3068 and ERAS-601;

SOS1 inhibitors including but not limited to BI1701963 and BAY-293;

CSF1R inhibitors (PLX3397, LY3022855, ) and CSF1R antibodies (IMC-054, RG7l55) ;

TGF beta receptor kinase inhibitor such as LY2157299;

BTK inhibitor such as ibrutinib; BCR-ABL inhibitors: Imatinib (CAS No. 152459-95-5) ; Inilotinib hydrochloride; Nilotinib (CAS No. 923288-95-3) ; Dasatinib (BMS-345825 CAS No. 302962-49-8) ; Bosutinib (SKI-606 CAS No. 380843-75-4) ; Ponatinib (AP24534 CAS No. 943319-70-8) ; Bafetinib (INNO406 CAS No. 859212-16-1) ; Danusertib (PHA-739358 CAS No. 827318-97-8) , AT9283 (CAS No. 896466-04-9) ; Saracatinib (AZD0530 CAS No. 379231-04-6) ; and PF-03814735 (CAS 942487-16-3) ;

ALK inhibitors: PF-2341066 (crizotinib) ; 5-chloro-N4- (2- (isopropyl-sulfonyl) phenyl) -N2- (2-methoxy-4- (4- (4-methylpiperazin-l-yl) piperidin-l-yl) phenyl) pyrimidine-2, 4- diamine; GSK1838705A (CAS No. 1116235-97-2) ; CH5424802 (CAS No. 1256580-46-7) ; Ceritinib (ZYKADIA CAS No. 1032900-25-6) ; TQ-B3139, and TQ-B3101;

PI3K inhibitors: 4- [2- (1H-indazol-4-yl) -6- [ [4- (methylsulfonyl) -piperazin-l-yl] methyl] thieno [3, 2-d] pyrimidin-4-yl] morpholine (also known as GDC 0941 and described in PCT Publication Nos. WO 09/036082 and WO 09/055730) , BEZ235 or NVP-BEZ235 (CAS No. 915019-65-7) , disclosed in PCT Publication No. WO 06/122806) ;

Vascular Endothelial Growth Factor (VEGF) receptor inhibitors: Bevacizumab (sold under the trademarkby Genentech/Roche) , axitinib, (N-methyl-2- [ [3- [ (E) -2-pyridin-2-ylethenyl] -lH-indazol-6-yl] sulfanyl] benzamide, also known as AG013736, and described in PCT Publication No. WO 01/002369) , Brivanib Alaninate ( (S) - ( (R) -l- (4- (4-fluoro-2-methyl-4H-indol-5-yloxy) -5-methylpyrrolo [2, l-f] [l, 2, 4] triazin-6-yloxy) propan-2-yl) 2-aminopropanoate, also known as BMS-582664) , motesanib (N- (2, 3-dihydro-3, 3-dimethyl-1H-indol-6-yl) -2- [ (4-pyridinylmethyl) amino] -3-pyridinecarboxamide, and described in PCT Publication No. WO 02/066470) , pasireotide (also known as SOM230, and described in PCT Publication No. WO 02/010192) , sorafenib (sold under the tradenameCAS No. 284461-73-0) ; or AL-2846;

MET inhibitor such as foretinib (CAS No. 849217-64-7) , cabozantinib (CAS No. 1140909-48-3) , capmatinib (CAS No. 1029712-80-8) , tepotinib (CAS No. 1100598-32-0) , savolitinib (CAS No. 1313725-88-0, or crizotinib (CAS No. 877399-52-5) ;

FLT3 inhibitors -sunitinib malate (CAS No. 341031-54-7, sold under the tradenameby Pfizer) ; PKC412 (CAS No. 120685-11-2, midostaurin) ; tandutinib (CAS No. 387867-13-2) , sorafenib (CAS No. 284461-73-0) , lestaurtinib (CAS No.: 111358-88-4) , KW-2449 (CAS No. 1000669-72-6) , quizartinib (AC220, CAS No. 950769-58-1) , or crenolanib (CAS No. 670220-88-9) ;

Epidermal growth factor receptor (EGFR) inhibitors: Gefitnib (sold under the tradename ) , N- [4- [ (3-chloro-4-fluorophenyl) amino] -7- [ [ (3S) -tetrahydro-3-furanyl] oxy] -6-quinazolinyl] -4 (dimethylamino) -2-butenamide, sold under the tradenameby Boehringer Ingelheim) , cetuximab (sold under the tradenameby Bristol-Myers Squibb) , or panitumumab (sold under the tradenameby Amgen) ;

HER2 receptor inhibitors: Trastuzumab (sold under the trademarkby Genentech/Roche) , neratinib (also known as HKI-272, (2E) -N- [4- [ [3-chloro-4- [ (pyridin-2-yl) methoxy] phenyl] amino] -3-cyano-7-ethoxyquinolin-6-yl] -4- (d imethylamino) but-2-enamide, and described PCT Publication No. WO 05/028443) , lapatinib (CAS No. 231277-92-2) or lapatinib ditosylate (CAS No: 388082-77-7 ) (sold under the trademarkby GlaxoSmithKline) ; or Trastuzumab emtansine (in the United States, ado-trastuzumab emtansine, trade name Kadcyla) -an antibody-drug conjugate consisting of the monoclonal antibody trastuzumab (Herceptin) linked to the cytotoxic agent mertansine (DM1) ;

HER dimerization inhibitors: Pertuzumab (sold under the trademarkby Genentech) ;

FGFR inhibitors: Erdafitinib (CAS No. 1346242-81-6) , Pemigatinib (CAS No. 1513857-77-6) or Infigratinib (CAS No. 872511-34-7)

Aurora kinase inhibitors: TAS-119 (CAS No. 1453099-83-6) , LY3295668 (CAS No. 1919888-06-4) , or alisertib (CAS No. 1028486-01-2) ;

CD20 antibodies: Rituximab (sold under the trademarksandby Genentech/Roche) , tositumomab (sold under the trademarksby GlaxoSmithKline) , or ofatumumab (sold under the trademarkby GlaxoSmithKline) ;

Tyrosine kinase inhibitors: Erlotinib hydrochloride (CAS No. 183319-69-9, sold under the trademarkby Genentech/Roche) , Linifanib (N- [4- (3-amino-1H-indazol-4-yl) phenyl] -N'- (2-fluoro-5-methylphenyl) urea, also known as ABT 869, available from Genentech) , sunitinib malate (CAS No. 341031-54-7, sold under the tradenameby Pfizer) , bosutinib (4- [ (2, 4-dichloro-5-methoxyphenyl) amino] -6-methoxy-7- [3- (4-methylpiperazin4-yl) propoxy] quinoline-3-carbonitrile, also known as SKI-606, and described in US Patent No. 6, 780, 996) , dasatinib (CAS No. 302962-49-8, sold under the tradenameby Bristol-Myers Squibb) , armala (CAS No. 444731-52-6, also known as pazopanib, sold under the tradenameby GlaxoSmithKline) , imatinib (CAS No. 152459-95-5) and imatinib mesylate (CAS No. 220127-57-1) (sold under the tradenamesandby Novartis) ;

DNA Synthesis inhibitors: Capecitabine (CAS No. 154361-50-9) (sold under the trademark by Roche) , gemcitabine hydrochloride (CAS No. 122111-03-9) (sold under the trademark by Eli Lilly and Company) , or nelarabine ( (2R3S, 4R, 5R) -2- (2-amino-6-methoxypurin-9-yl) -5- (hydroxymethyl) oxolane-3, 4-diol, sold under the tradenamesandby GlaxoSmithKline) ;

Antineoplastic agents: oxaliplatin (CAS No. 61825-94-3) (sold under the tradename ay Sanofi-Aventis and described in US Patent No. 4, 169, 846) ;

Human Granulocyte colony-stimulating factor (G-CSF) modulators: Filgrastim (sold under the tradenameby Amgen) ;

Immunomodulators: Afutuzumab (available from) , pegfilgrastim (sold under the tradenameby Amgen) , lenalidomide (CAS No. 191732-72-6, also known as CC-5013, sold under the tradename) , or thalidomide (CAS No. 50-35-1, sold under the tradename );

CD40 inhibitors: Dacetuzumab (also known as SGN-40 or huS2C6, available from Seattle Genetics, Inc) ;

Pro-apoptotic receptor agonists (PARAs) : Dulanermin (also known as AMG-951, available from Amgen/Genentech) ;

Hedgehog antagonists: 2-chloro-N- [4-chloro-3- (2-pyridinyl) phenyl] -4- (methylsulfony 1) -benzamide (also known as GDC-0449, and described in PCT Publication No. WO 06/028958) ;

Phospholipase A2 inhibitors: Anagrelide (CAS No. 58579-51-4, sold under the tradename );

BCL-2 inhibitors: 4- [4- [ [2- (4-chlorophenyl) -5, 5-dimethyl-l-cyclohexen-l-yl] met hyl] -1-piperazinyl] -N- [ [4- [ [ (lR) -3- (4-morpholinyl) -l- [ (phenylthio) m ethyl] propyl] amino] -3- [ (trifluoromethyl) sulfonyl] phenyl] sulfonyl] benzamide (also known as ABT-263 and described in PCT Publication No. WO 09/155386) ;

MCL-1 inhibitors: MIK665 (CAS No. 1799631-75-6, S64315) , AMG 397, and AZD5991 (CAS No. 2143010-83-5) ; Aromatase inhibitors: Exemestane (CAS No. 107868-30-4, sold under the trademarkby Pfizer) , letrozole (CAS No. 112809-51-5, sold under the tradename by Novartis) , or anastrozole (CAS No. 120511-73-1, sold under the tradename) ;

Topoisomerase I inhibitors: Irinotecan (CAS No. 97682-44-5, sold under the trademark by Pfizer) , topotecan hydrochloride (CAS No. 119413-54-6, sold under the tradename by GlaxoSmithKline) ;

Topoisomerase II inhibitors: etoposide (CAS No. 33419-42-0, also known as VP-

16 and Etoposide phosphate, sold under the tradenames and ) , or teniposide (CAS No. 29767-20-2, also known as VM-26, sold under the tradename );mTOR inhibitors: Temsirolimus (CAS No. 162635-04-3, sold under the tradenameby Pfizer) , ridaforolimus (CAS No. 572924-54-0, formally known as deferolimus, AP23573 and MK8669, and described in PCT Publication No. WO 03/064383) , or everolimus (CAS No. 159351-69-6, sold under the tradenameby Novartis) ;

Proteasome inhibitor such as carfilzomib (CAS No. 868540-17-4) , MLN9708 (CAS No. 1201902-80-8) , delanzomib (CAS No. 847499-27-8) , or bortezomib (CAS No. 179324-69-7) ;

BET inhibitors such as INCB054329 (CAS No. 1628607-64-6) , OTX015 (CAS No. 202590-98-5) , or CPI-0610 (CAS No. 1380087-89-7) ;

LSD1 inhibitors such as GSK2979552, or INCB059872;

HIF-2α inhibitors such as PT2977 (1672668-24-4) , NKT2152, or PT2385 (CAS No. 1672665-49-4) ;

Osteoclastic bone resorption inhibitors: 1-hydroxy-2-imidazol-l-yl-phosphonoethyl) phosphonic acid monohydrate (sold under the tradenameby Novartis) ;

CD33 Antibody Drug Conjugates: Gemtuzumab ozogamicin (sold under the tradename by Pfizer/Wyeth) ;

CD22 Antibody Drug Conjugates: Inotuzumab ozogamicin (also referred to as CMC-544 and WAY-207294, available from Hangzhou Sage Chemical Co., Ltd. ) ;

CD20 Antibody Drug Conjugates: Ibritumomab tiuxetan (sold under the tradename );

Somatostain analogs: octreotide (also known as octreotide acetate, sold under the tradenames and Sandostatin) ;

Synthetic Interleukin-11 (IL-l 1) : oprelvekin (sold under the tradenameby Pfizer/Wyeth) ;

Synthetic erythropoietin: Darbepoetin alfa (sold under the tradenameby Amgen) ;

Receptor Activator for Nuclear Factor k B (RANK) inhibitors: Denosumab (sold under the tradenameby Amgen) ;

Thrombopoietin mimetic peptibodies: Romiplostim (sold under the tradename by Amgen;

Cell growth stimulators: Palifermin (sold under the tradenameby Amgen) ;

Anti-insulin-like Growth Factor-l receptor (IGF-1R) antibodies: Figitumumab (also known as CP-751, 871, available from ACC Corp) , robatumumab (CAS No. 934235-44-6) ;

Anti-CSl antibodies: Elotuzumab (HuLuc63, CAS No. 915296-00-3) ;

CD52 antibodies: Alemtuzumab (sold under the tradename) ;

Histone deacetylase inhibitors: Voninostat (sold under the tradenameby Merck) ;

Alkylating agents: Temozolomide (sold under the tradenamesandby Schering-Plough/Merck) , dactinomycin (also known as actinomycin-D and sold under the tradename ) , melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under the tradename) , altretamine (also known as hexamethylmelamine (HMM) , sold under the tradename) , carmustine (sold under the tradename) , bendamustine (sold under the tradename) , busulfan (sold under the tradenamesand ) , carboplatin (sold under the tradename) , lomustine (also known as CCNU, sold under the tradename) , cisplatin (also known as CDDP, sold under the tradenames and-AQ) , chlorambucil (sold under the tradename) , cyclophosphamide (sold under the tradenamesand) , dacarbazine (also known as DTIC, DIC and imidazole carboxamide, sold under the tradename DTIC -) , altretamine (also known as hexamethylmelamine (HMM) sold under the tradename) , ifosfamide (sold under the tradename) , procarbazine (sold under the tradename) , mechlorethamine (also known as nitrogen mustard, mustine and mechloroethamine hydrochloride, sold under the tradename ) , streptozocin (sold under the tradename) , thiotepa (also known as thiophosphoamide, TESPA and TSPA, sold under the tradename

Biologic response modifiers: bacillus calmette-guerin (sold under the tradenamesandBCG) , or Denileukin diftitox (sold under the tradename) ;

Anti-tumor antibiotics: doxorubicin (sold under the tradenamesand) , bleomycin (sold under the tradename) , daunorubicin (also known as dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, sold under the tradename) , daunorubicin liposomal (daunorubicin citrate liposome, sold under the tradename) , mitoxantrone (also known as DHAD, sold under the tradename) , epirubicin (sold under the tradename Ellence^TM) , idarubicin (sold under the tradenamesIdamycin) , or mitomycin C (sold under the tradename) ;

Anti -microtubule agents: Estramustine (CAS No. 52205-73-9, sold under the tradename );

Cathepsin K inhibitors: Odanacatib (CAS No. 603139-19-1, also know as MK-0822 available from Lanzhou Chon Chemicals, ACC Corp., and ChemieTek, and described in PCT Publication no. WO 03/075836) ;

Epothilone B analogs: Ixabepilone (CAS No. 219989-84-1, sold under the tradename by Bristol-Myers Squibb) ;

Heat Shock Protein (HSP) inhibitors: Tanespimycin (l7-allylamino-l7-demethoxygeldanamycin, also known as KOS-953 and 17-AAG, available from SIGMA, and described in US Patent No. 4, 261, 989) , NVP-HSP990 (CAS No. 934343-74-5) , AUY922 (CAS No. 747412-49-3) , AT13387 (CAS No. 912999-49-6) , STA-9090 (CAS No. 888216-25-9) , Debio 0932, KW-2478 (CAS No. 819812-04-9) , XL888 (CAS No. 1149705-71-4) , CNF2024 (CAS No. 848695-25-0) , and TAS-116 (CAS No. 1260533-36-5) ;

TpoR agonists: Eltrombopag (sold under the tradenamesandby GlaxoSmithKline) ;

Anti-mitotic agents: Docetaxel (CAS No. 114977-28-5, sold under the tradenameby Sanofi-Aventis) ; Adrenal steroid inhibitors: aminoglutethimide (CAS No. 125-84-8, sold under the tradename) ;

Anti-androgens: Nilutamide (CAS No. 63612-50-0, sold under the tradenamesand) , bicalutamide (CAS No. 90357-06-5, sold under tradename) , or flutamide (CAS No. 13311-84-7, sold under the tradename Fulexin^TM) ;

Androgens: Fluoxymesterone (CAS No. 76-43-7, sold under the tradename) ;

CDK (CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, or CDK9) inhibitors including but not limited to: Alvocidib (CAS No. 146426-40-6, pan-CDK inhibitor, also known as flovopirdol or HMR-1275, 2- (2-chlorophenyl) -5, 7-dihydroxy-8- [ (3S, 4R) -3-hydroxy-l-methyl -4-piperidinyl] -4-chromenone, and described in US Patent No. 5,621,002) ;

CDK2 inhibitor PF-07104091;

CDK4/6 inhibitors: pabociclib (CAS No. 827022-33-3) , ribociclib (CAS No. 1211441-98-3) , abemaciclib (CAS No. 1231929-97-7) , PF-06873600 (CAS No. 2185857-97-8) , NUV-422 and Trilaciclib (CAS No. 1374743-00-6) ;

CDK7 inhibitors CT7001 (CAS No. 1805789-54-1) and SY-1365 (CAS No. 1816989-16-8) ;

CDK9 inhibtiors AZD 4573 (CAS No. 2057509-72-3) , P276-00 (CAS No. 920113-03-7) , AT7519 (CAS No. 844442-38-2) , CYC065 (CAS No. 1070790-89-4) or TP-1287;

Gonadotropin-releasing hormone (GnRH) receptor agonists: Leuprolide or leuprolide acetate (sold under the tradenamesby Bayer AG, by Sanofi-Aventis andby Abbott Lab) ;

Taxane anti-neoplastic agents: Cabazitaxel (l-hydroxy-7, 10 -dimethoxy-9-oxo-5, 20-epoxytax-11-ene-2a, 4, 13a-triyl-4-acetate-2-benzoate-13- [ (2R, 3S) -3- { [ (tert-butoxy) carbonyl] -amino} -2-hydroxy-3-phenylpropanoate) , or larotaxel ( (2a, 3x, 4a, 5b, 7a, 10b, 13a) -4, 10-bis (acetyloxy) -l3- ( { (2R, 3S) -3- [ (tert-butoxycarbonyl) amino] -2-hydroxy-3-phenylpropanoyl} oxy) -l-hydroxy-9-oxo-5, 20-epoxy-7, l9-cyclotax-11-en-2-ylbenzoate) ;

5HTla receptor agonists: Xaliproden (also known as SR57746, l- [2- (2-naphthyl) ethyl] -4- [3- (trifluoromethyl) phenyl] -l, 2, 3, 6-tetrahydropyridine, and described in US Patent No. 5,266,573) ;

HPC vaccines: sold by GlaxoSmithKline, sold by Merck;

Iron Chelating agents: Deferasinox (CAS No. 201530-41-8, sold under the tradename by Novartis) ;

Anti-metabolites: Claribine (2-chlorodeoxyadenosine, sold under the tradename) , 5-fluorouracil (sold under the tradename) , 6-thioguanine (sold under the tradename ) , pemetrexed (sold under the tradename) , cytarabine (also known as arabinosylcytosine (Ara-C) , sold under the tradename Cytosar-) , cytarabine liposomal (also known as Liposomal Ara-C, sold under the tradename DepoCyt^TM) , decitabine (sold under the tradename) , hydroxyurea (sold under the tradenamesDroxia^TM and Mylocel^TM) , fludarabine (sold under the tradename) , floxuridine (sold under the tradename) , cladribine (also known as 2-chlorodeoxyadenosine (2-CdA) sold under the tradename Leustatin^TM) , methotrexate (also known as amethopterin, methotrexate sodim (MTX) , sold under the tradenames and Trexall^TM) , or pentostatin (sold under the tradename) ;

Bisphosphonates: Pamidronate (CAS No. 57248-88-1, sold under the tradename) , zoledronic acid CAS No. 118072-93-8 (sold under the tradename) ;

Demethylating agents: 5-azacitidine (CAS No. 320-67-2, sold under the tradename) , decitabine (CAS No. 2353-33-5, sold under the tradename) ;

Plant Alkaloids: Paclitaxel protein-bound (sold under the tradename) , vinblastine (also known as vinblastine sulfate, vincaleukoblastine and VLB, sold under the tradenames Alkaban-and) , vincristine (also known as vincristine sulfate, LCR, and VCR, sold under the tradenamesand Vincasar) , vinorelbine (sold under the tradename) , or paclitaxel (sold under the tradenames Taxol and Onxal^TM) ;

Retinoids: Ali tretinoin (sold under the tradename) , tretinoin (all-trans retinoic acid, also known as ATRA, sold under the tradename) , Isotretinoin (13-cis-retinoic acid, sold under the tradenames and ) , or bexarotene (sold under the tradename) ;

Glucocorticosteroids: Hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and sold under the tradenames Ala-Hydrocortisone Phosphate, Solu-Hydrocortand) , dexamethazone ( (8S, 9R, 10S, 11S, 13S, 14S, 16R, 17R) -9-fluoro-11, 17-dihydroxy-17- (2-hydroxyacetyl) -10, 13, 16-trimethyl-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [a] phenanthren-3-one) , prednisolone (sold under the tradenames Delta- and) , prednisone (sold under the tradenamesLiquid and) , or methylprednisolone (also known as 6-Methylprednisolone, Methylprednisolone Acetate, Methylprednisolone Sodium Succinate, sold under the tradenames M-and Solu-) ;

Cytokines: interleukin-2 (also known as aldesleukin and IL-2, sold under the tradename ) , interleukin-11 (also known as oprevelkin, sold under the tradename) , alpha interferon alfa (also known as IFN-alpha, sold under the tradenamesA, and Roferon-) ;

Estrogen receptor downregulators: Fulvestrant (CAS No. 129453-61-8, sold under the tradename) ;

Anti-estrogens: tamoxifen (CAS No. 10540-29-1, sold under the tradename) ; or Toremifene (CAS No. 89778-27-8, sold under the tradename) ;

Selective estrogen receptor modulators (SERMs) : Raloxifene (CAS No. 84449-90-1, sold under the tradename) ;

Leutinizing hormone releasing hormone (LFfRH) agonists: Goserelin (CAS No. 145781-92-6, sold under the tradename) ; Progesterones: megestrol (also known as megestrol acetate, CAS No. 595-33-5, sold under the tradename) ;

Miscellaneous cytotoxic agents: Arsenic trioxide (sold under the tradename) , or asparaginase (also known as L-asparaginase, Erwinia L-asparaginase, sold under the tradenames and) ;

Exemplary immune checkpoint inhibitors include inhibitors (smack molecules or biologies) against immune checkpoint molecules such as CD27, CD28, CD40, CD 122, CD96, CD73, CD39, CD47, 0X40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM kinase, arginase, CD137 (also known as 4-1BB) , ICOS, A2AR, A2BR, HIF-2a, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, PD-l, PD-L1 and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, 0X40, GITR, CD137 and STING. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from B7-H3, B7-H4, BTLA, CTLA-4, IDO, TDO, Arginase, KIR, LAG3, PD-l, TIM3, CD96, TIGIT and VISTA. In some embodiments, the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD 160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-l, e.g., an anti-PD-l monoclonal antibody. In some embodiments, the anti-PD-l monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475) , pidilizumab, SHR-1210, PDR001, or AMP -224. In some embodiments, the anti-PD-l monoclonal antibody is nivolumab, or pembrolizumab or PDR001. In some embodiments, the anti -PD 1 antibody is pembrolizumab.

In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-Ll monoclonal antibody. In some embodiments, the anti-PD-Ll monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446) , or MSB0010718C. In some embodiments, the anti-PD-Ll monoclonal antibody is MPDL3280A (atezolizumab) or MEDI4736 (durvalumab) . In some embodiments, the anti-PD-L1 small molecule inhibitor is INCB86550.

In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016 or LAG525. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518 or, MK-4166, INCAGN01876 or MK-1248. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of 0X40, e.g., an anti-OX40 antibody or OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MED 10562 or, INCAGN01949, GSK2831781, GSK-3174998, MOXR-0916, PF-04518600 or LAG525. In some embodiments, the OX40L fusion protein is MEDI6383.

Compounds of the invention can also be used to increase or enhance an immune response, including increasing the immune response to an antigen; to improve immunization, including increasing vaccine efficacy; and to increase inflammation. In some embodiments, the compounds of the invention can be sued to enhance the immune response to vaccines including, but not limited, Listeria vaccines, oncolytic viral vaccines, and cancer vaccines such as (granulocyte-macrophage colony-stimulating factor (GM-CF) gene-transfected tumor cell vaccine) . Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses. Other immune-modulatory agents also include those that block immune cell migration such as antagonists to chemokine receptors, including CCR2 and CCR4; Sting agonists and Toll receptor agonists. Other anti-cancer agents also include those that augment the immune system such as adjuvants or adoptive T cell transfer. Compounds of this application may be effective in combination with CAR (Chimeric antigen receptor) T cell treatment as a booster for T cell activation.

A compound of the invention can also be used in combination with the following adjunct therapies: Anti-nausea drugs: NK-l receptor antagonists: Casopitant (sold under the tradenames andby GlaxoSmithKline) ; and Cytoprotective agents: Amifostine (sold under the tradename) , leucovorin (also known as calcium leucovorin, citrovorum factor and folinic acid) . The disclosure of the PCT applications referred to herein above are incorporated herein by reference in their entirety.

Examples

The following preparations of intermediates and compounds of of the disclosure (Examples) are given to enable those skilled in the art to more clearly understand and to practice the present disclosure. They should not be considered as limiting the scope of the disclosure, but merely as being illustrative and representative thereof.

Synthetic Examples

Intermediate 1

Synthesis of tert-butyl (1R, 5S) -3- (2-chloro-7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

Step 1: 8-fluoro-7- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) pyrido [4, 3-d] -pyrimidine-2, 4-diol

To a mixture of 7-chloro-8-fluoropyrido [4, 3-d] pyrimidine-2, 4-diol (4.0 g, 18.6 mmol, 1.0 eq. ) and ( (2-fluoro-8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) -triisopropylsilane (10.9 g, 24.1 mmol, 1.3 eq. ) in EtOH (150 mL) and H₂O (50 mL) were added CATACXIUM A Pd G3 (2.4 g, 3.3 mmol, 0.18 eq. ) , K₃PO₄ (11.7 g, 55.1 mmol, 3.0 eq. ) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 80 ℃ under nitrogen atmosphere. After cooling to rt, the mixture was added water, and then extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na₂SO₄, filtered and then concentrated. The residue was purified by silica gel column chromatography, eluted with MeOH/DCM (0-10%) , to afford the title compound (5.5 g) .

Step 2: 7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidine-2, 4-diol

A mixture of 8-fluoro-7- (7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) pyrido [4, 3-d] pyrimidine-2, 4-diol (10.0 g, 19.8 mmol, 1.0 eq. ) and CsF (12.0 g, 79.0 mmol, 4.0 eq. ) in DMF (100 mL) was stirred for 1 h at 50 ℃ under nitrogen atmosphere. After cooling to rt, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography, eluted with MeOH/DCM (0-10%) , to afford the title compound (6.0 g) .

Step 3: 2, 4-dichloro-7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidine

To a solution of POCl₃ (15.8 g, 103.0 mmol, 30.3 eq. ) and DIPEA (13.4 g, 103.7 mmol, 30.5 eq. ) was added 7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyrido [4, 3-d] -pyrimidine-2, 4-diol (1.2 g, 3.4 mmol, 1.0 eq. ) in portions at 0-5 ℃ and the resulting mixture was stirred for 1 h. The mixture was concentrated and the residue was diluted with ice water, and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na₂SO₄, filtered and concentrated to afford the title compound (1.5 g, crude) as a brown solid, which was used for next step without further purification.

Step 4: tert-butyl (1R, 5S) -3- (2-chloro-7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

To a solution of 2, 4-dichloro-7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyrido- [4, 3-d] pyrimidine (1.5 g, 3.9 mmol, 1.0 eq., crude) in DCM (30 mL) was added DIEA (1.1 g, 8.5 mmol, 2.2 eq. ) dropwise at -40 ℃. After stirring for 5 min at -40 ℃, a solution of tert-butyl (1R, 5S) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (870 mg, 4.1 mmol, 1.1 eq. ) in THF (5 mL) was added dropwise and the resulting mixture was stirred for additional 15 min at -40 ℃. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography, eluted with EA/PE (0-50%) , to afford the title compound (770 mg) .

Step 5: tert-butyl (1R, 5S) -3- (7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-methoxy-6-methylenetetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

Intermediate 2

Synthesis of ( (5S, 7aS) -5- ( ( (tert-butyldiphenylsilyl) oxy) methyl) -2-methylenetetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol

Step1: (2S) -tert-butyl 2- (hydroxymethyl) -5-methoxypyrrolidine-1-carboxylate

To a solution of (S) -1-tert-butyl 2-methyl 5-oxopyrrolidine-1, 2-dicarboxylate (150 g, 617 mmol) in DCM (900 mL) was added DIBAL-H (1 M, 2.47 L) and the resulting mixture was stirred at -78 ℃ for 0.5 h, then at 20℃ for 2 h. After cooling to 0 ℃, methyl alcohol (3000 mL) and 2 M HCl (5000 mL) were added. The mixture was stirred for 2 h at room temperature and then extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography, eluted with EA/PE (0-50%) , to afford the title compound (42.0 g, 181 mmol, 36.8%yield) was obtained as a yellow oil.

Step 2: (5S) -tert-butyl 2-cyano-5- (hydroxymethyl) pyrrolidine-1-carboxylate

To a solution of (2S) -tert-butyl 2- (hydroxymethyl) -5-methoxypyrrolidine-1-carboxylate (48.0 g, 208 mmol) in DCM (500 mL) at -70 ℃ was added TMSCN (51.5 g, 519 mmol, 64.9 mL) dropwise and then BF₃. Et₂O (64.8 g, 457 mmol, 56.4 mL) . The resulting mixture was then stirred at -70 ℃ for 1 h and then. then quenched with sat. NahCO₃ aq. solution. The mixture was then extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography, eluted with EA/PE (0-20%) , to afford the title compound (31.0 g) .

Step3: tert-butyl (2S) -2- [ [tert-butyl (diphenyl) silyl] oxymethyl] -5-cyano-pyrrolidine-1-carboxylate

To a solution of tert-butyl (5S) -2-cyano-5- (hydroxymethyl) pyrrolidine-1-carboxylate (50 g, 220 mmol, 1 eq) in THF (500 mL) was added imidazole (37.6 g, 552.43 mmol, 2.5 eq) and tert-butyl-chlorodiphenylsilane (66.8 g, 243 mmol, 62.4 mL, 1.1 eq) at 0 ℃. The mixture was stirred at 20 ℃for 12 h and then quenched with H₂O, and extracted with EA. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography, eluted with EA/PE (0-20%) , to afford the title compound (69.0 g) .

Step 4: (5S) -1-tert-butyl 2-methyl 5- ( ( (tert-butyldiphenylsilyl) oxy) methyl) pyrrolidine-1, 2-dicarboxylate

A mixture of tert-butyl (2S) -2- [ [tert-butyl (diphenyl) silyl] oxymethyl] -5-cyano-pyrrolidine-1-carboxylate (69.0 g, 148 mmol, 1 eq) and K₂CO₃ (26.6 g, 193 mmol, 1.3 eq) in MeOH (500 mL) was stirred at 50 ℃ for 12 h under N₂ atmosphere. The mixture was acidified with 1.0 M HCl aq. to pH=4 and then extracted with EA. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography, eluted with EA/PE (0-15%) , to afford the title compound (12 g, 19.53 mmol) .

Step 5: 1- (tert-butyl) 2-methyl (2S, 5S) -5- ( ( (tert-butyldiphenylsilyl) oxy) methyl) -2- (2- (chloromethyl) allyl) pyrrolidine-1, 2-dicarboxylate

To a solution of (5S) -1-tert-butyl 2-methyl 5- ( ( (tert-butyldiphenylsilyl) oxy) methyl) -pyrrolidine-1, 2-dicarboxylate (12.0 g, 24.1 mmol, 1 eq) in THF (100 mL) was added LiHMDS (1 M, 48.22 mL, 2 eq) at -70 ℃ and the mixture was stirred at -70 ℃ for 15 min. 3-Chloro-2- (chloromethyl) prop-1-ene (4.52 g, 36.1 mmol, 4.19 mL, 1.5 eq) was added dropwise at -70 ℃ under nitrogen atmosphere and the resulting mixture was stirred 16 h at 20 ℃. The mixture was quenched with sat. NahCO₃ aq. and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography, eluted with EA/PE (0-10%) , to afford the title compound (11 g) .

Step 6: methyl (5S, 7aS) -5- ( ( (tert-butyldiphenylsilyl) oxy) methyl) -2-methylenetetrahydro-1H-pyrrolizine-7a (5H) -carboxylate

To a solution of 1- (tert-butyl) 2-methyl (2S, 5S) -5- ( ( (tert-butyldiphenylsilyl) oxy) methyl) -2- (2- (chloromethyl) allyl) pyrrolidine-1, 2-dicarboxylate (10.7 g, 18.2 mmol, 1 eq) in DCM (90 mL) was added TFA (45 mL) at 0 ℃ and the resulting mixture was stirred at 20 ℃ for 2 h. The reaction was quenched by adding sat. aq. NaHCO₃ solution at 0 ℃ and extracted with DCM. The combined organic layers were washed with brine, dried over Na₂SO₄ filtered and concentrated. The residue was purified by column chromatography eluted with EA/PE (0-10%) , to afford the title compound (3.2 g, crude) .

Step 7: ( (5S, 7aS) -5- ( ( (tert-butyldiphenylsilyl) oxy) methyl) -2-methylenetetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol

To a solution of LiAlH₄ (540 mg, 14.2 mmol, 2 eq) in THF (20 mL) was added dropwise methyl (5S, 7aS) -5- ( ( (tert-butyldiphenylsilyl) oxy) methyl) -2-methylenetetrahydro-1H-pyrrolizine-7a (5H) -carboxylate (3.2 g, 7.12 mmol, 1 eq) in THF (10 mL) at -40 ℃ and the resulting mixture was stirred at -40 ℃ for 1 h. After cooling the mixture to 0 ℃, the mixture was quenched by adding Na₂SO₄.10H₂O. The mixture was then filtered and concentrated under reduced pressure to give the title compound (2.83 g, crude) . MS (ESI) m/z = 422.6 [M+1] ⁺

Intermediate 3

Synthesis of ( (5S, 7aS) -5- (1- ( (tert-butyldiphenylsilyl) oxy) ethyl) -2-methylenetetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol

Step1: (2S) -tert-butyl 2- (hydroxymethyl) -5-methoxypyrrolidine-1-carboxylate

To a solution of (S) -1-tert-butyl 2-methyl 5-oxopyrrolidine-1, 2-dicarboxylate (20 g, 82.3 mmol, 1.0 equiv) in DCM (200 mL) was added DIBAL-H (1 M, 329.2 mL) at -78 ℃ and the resulting mixture was stirred at -78 ℃ for 0.5 hrs and at 20 ℃ for 2 h. After cooling to 0 ℃, to the above solution were added methyl alcohol (320 mL) and 2.0 M HCl aq. solution (320 mL) dropwise at 0 ℃. The resulting mixture was stirred for 2 h at room temperature and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography, eluted with EA/PE (0-50%) , to afford the title compound (14.0 g) .

Step 2: tert-butyl (2S) -2-formyl-5-methoxypyrrolidine-1-carboxylate

To a solution of tert-butyl (2S) -2- (hydroxymethyl) -5-methoxypyrrolidine-1-carboxylate (9.0 g, 38.9 mmol, 1 eq) in DCM (90 mL) was added Dess-Martin periodinane (19.8 g, 46.7 mmol, 1.2 eq) and the resulting mixture was stirred at 25 ℃ for 12 h. The mixutre was quenched with sat. NahCO₃ aq. solution. The mixture was filtrated and the filtratewas diluted with water, and then extracted with DCM. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated, and the residue was purified by column chromatography, eluted with EA/PE (0-25%) to afford the title compound (4.9 g) .

Step 3: tert-butyl (2S) -2- (1-hydroxyethyl) -5-methoxypyrrolidine-1-carboxylate

To a solution of tert-butyl (2S) -2-formyl-5-methoxypyrrolidine-1-carboxylate (4.9 g, 21.4 mmol, 1.0 eq) in THF (50 mL) was added dropwise CH₃MgCl in THF (3.0 M, 64.1mmol, 21.4 mL, 3.0 eq) at 0 ℃ and the resulting mixture was stirred at 25 ℃ for 1 h. After coolign to 0 ℃, the mixture was quenched by adding sat. Nh₄Cl aq. solution at 0 ℃ and then extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography, eluted with EA/PE (0-20%) , to afford the title compound (3.7 g) .

Step 3: tert-butyl (5S) -2-cyano-5- (1-hydroxyethyl) pyrrolidine-1-carboxylate

To a solution of tert-butyl (2S) -2- (1-hydroxyethyl) -5-methoxypyrrolidine-1-carboxylate (3.7 g, 15.1 mmol, 1.0 eq) in DCM (35 mL) was added dropwise TMSCN (3.7g, 37.7 mmol, 2.5 eq) at -70 ℃ and then BF₃. Et₂O (4.7g, 33.2 mmol, 2.2 eq) at -70 ℃. The resulting mixture was stirred at -70 ℃ for 1 h. After warming to 0 ℃, the mixture was quenched with sat. NahCO₃ aq. solution and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography, eluted with EA/PE (0-30%) , to afford the title compound (2.7 g) .

Step 4: 1- (tert-butyl) 2-methyl (5S) -5- (1-hydroxyethyl) pyrrolidine-1, 2-dicarboxylate

A mixture of tert-butyl (5S) -2-cyano-5- (1-hydroxyethyl) pyrrolidine-1-carboxylate (2.7 g, 11.2 mmol, 1 eq) , K₂CO₃ (3.1g, 22.5 mmol, 2.0 eq) in MeOH (25 mL) was stirred at 25 ℃ for 3 h under N₂ atmosphere. The mixture was quenched with 1.0 M HCl aq. solution to pH= 2 and then stirred at 25 ℃ overnight. The mixture was basified to pH=8 by adding sat. NahCO₃ aq. solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography, eluted with EA/PE (0-35%) to afford the title compound (1.6 g) .

Step 5: 1- (tert-butyl) 2-methyl (5S) -5- (1- ( (tert-butyldiphenylsilyl) oxy) ethyl) pyrrolidine 1, 2-dicarboxylate

To a solution of 1- (tert-butyl) 2-methyl (5S) -5- (1-hydroxyethyl) pyrrolidine-1, 2-dicarboxylate (1.6 g, 5.9 mmol, 1.0 eq) in DMF (2 mL) was added imidazole (1.2 g, 17.6 mmol, 3.0 eq) and tert-butyl-chlorodiphenylsilane (3.2 g, 11.7 mmol, 2.0 eq) at 0 ℃ and the resulting mixture was stirred at 20 ℃ for 12 h. The mixutre was quenched with waterand extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO4, filtered and concentrated. The residue was purified by column chromatography, eluted with EA/PE (0-20%) to afford crude compound. The crude compound was purified by reverse column to afford the title compound (2.6 g) as a colorless oil.

Step 6: ( (5S, 7aS) -5- (1- ( (tert-butyldiphenylsilyl) oxy) ethyl) -2-methylenetetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol

The title compound was prepared by proceeding analogously as described in Intermediate 2, Steps 5-7, using 1- (tert-butyl) 2-methyl (5S) -5- (1- ( (tert-butyldiphenylsilyl) oxy) ethyl) -pyrrolidine-1, 2-dicarboxylate instead of (5S) -1-tert-butyl 2-methyl 5- ( ( (tert-butyldiphenylsilyl) -oxy) methyl) pyrrolidine-1, 2-dicarboxylate in Step 5.

Intermediate 4

Synthesis of ( (5S, 7aS) -5- (2- ( (tert-butyldiphenylsilyl) oxy) ethyl) -2-methylenetetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol

Step 1: 1- (tert-butyl) 2-methyl (2R, 5S) -5-allylpyrrolidine-1, 2-dicarboxylate

To a stirred solution of 1- (tert-butyl) 2-methyl (2R) -5-methoxypyrrolidine-1, 2-dicarboxylate (J. Org. Chem. 2008, 73, 1661) (25 g, 96 mmol, 1 equiv) and allyltrimethylsilane (49.60 g, 434 mmol, 4.5 equiv) in DCM (250 mL) was added TiCl₄ (18.29 g, 96 mmol, 1 equiv) dropwise at -78 ℃ and the resulting mixture was stirred for 1 h at -78 ℃. The reaction mixture was basified to pH=7 with saturated NahCO₃ aq. solution. The mixture was filtered and the filtrate was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-10%) to afford the title compound (10 g) .

Step 2: 1- (tert-butyl) 2-methyl (2R, 5S) -5- (2-oxoethyl) pyrrolidine-1, 2-dicarboxylate

To a solution of 1-tert-butyl 2-methyl (2R, 5S) -5- (prop-2-en-1-yl) pyrrolidine-1, 2-dicarboxylate (10 g, 37 mmol, 1 equiv) in THF (120 mL) and H₂O (40 mL) were added K₂OsO₄.2H₂O (1.36 g, 3.7mmol, 0.1 equiv) and NaIO₄ (23.80 g, 111 mmol, 3.0 equiv) at 0 ℃. The resulting mixture was stirred for 16 h at room temperature under air atmosphere. The mixture was then filtered and the filter cake was washed with EtOAc. The filtrate was extracted with EtOAc. The combined organic layers were washed with NahSO₃ aq. solution and brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-50%) to afford the title compound (7 g) .

Step 3: 1- (tert-butyl) 2-methyl (2R, 5S) -5- (2-hydroxyethyl) pyrrolidine-1, 2-dicarboxylate

To a stirred solution of 1- (tert-butyl) 2-methyl (2R, 5S) -5- (2-oxoethyl) pyrrolidine-1, 2-dicarboxylate (7 g, 25 mmol, 1 equiv) in MeOH (15 mL) was added NaBH₄ (1.95 g, 51 mmol, 2 equiv) in portions at 0 ℃ and the resulting mixture was stirred for 30 min. at 0 ℃. The mixture was acidified to pH=6 with 2.0 M HCl aq. solution and then concentrated under reduced pressure. The mixture was then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-50%) to afford the title compound (7 g) .

Step 4: 1- (tert-butyl) 2-methyl (2R, 5S) -5- (2- ( (tert-butyldiphenylsilyl) oxy) ethyl) pyrrolidine-1, 2-dicarboxylate

To a stirred solution of 1- (tert-butyl) 2-methyl (2R, 5S) -5- (2-hydroxyethyl) pyrrolidine-1, 2-dicarboxylate (7 g, 25 mmol, 1 equiv) and TBDPSCl (8.45 g, 30 mmol, 1.2 equiv) in DCM (150 mL) was added imidazole (2.62 g, 38 mmol, 1.5 equiv) in portions at room temperature and the resulting mixture was stirred for 2 h at room temperature. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluted with THF/PE (0-10%) to afford the title compound (7.0 g) .

Step 5: ( (5S, 7aS) -5- (2- ( (tert-butyldiphenylsilyl) oxy) ethyl) -2-methylenetetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol

The title compound was prepared by proceeding analogously as described in Intermediate 2, Steps 5-7, using 1- (tert-butyl) 2-methyl (2R, 5S) -5- (2- ( (tert-butyldiphenylsilyl) oxy) -ethyl) pyrrolidine-1, 2-dicarboxylate instead of (5S) -1-tert-butyl 2-methyl 5- ( ( (tert-butyldiphenylsilyl) oxy) methyl) pyrrolidine-1, 2-dicarboxylate in Step 5.

Intermediate 5

Synthesis of 2, 3, 4, 5a, 6, 7, 8, 8a-octahydro- [1, 4] dioxepino [2, 3-c] pyrrole

Step 1: ethyl 2- [benzyl- (2-ethoxy-2-oxo-ethyl) amino] acetate

To a stirred solution of benzylamine (10.0 g, 93.3 mmol, 1.0 eq) in EtOH (300 mL) was added ethyl 2-bromoacetate (31.1 g, 186.2 mmol, 2.0 eq) and K₂CO₃ (77.3 g, 559 mmol, 6.0 eq) at room temperature. After stirring at 20 ℃ for 2 h, the reaction mixture was filtered, concentrated and then purified by silica gel column chromatography, eluted with EA/PE (5-10%) , to give the title compound (13.5 g) .

Step 2: diethyl 1-benzyl-3, 4-dihydroxy-pyrrole-2, 5-dicarboxylate

To a stirred solution of NaOEt in EtOH (2.86 M, 100 mL) was added a solution of ethyl 2- [benzyl- (2-ethoxy-2-oxo-ethyl) amino] acetate (10.5 g, 37.6 mmol, 1.0 eq) and diethyl oxalate (6.04 g, 41.3 mmol, 1.1 eq) in EtOH (100 mL) at 80 ℃. After stirring at 80 ℃ for 4 h, the reaction mixture was cooled to 0℃, acidified to pH = 5 with AcOH and then filtered. The solid cake was slurred in EtOH (30 mL) at 60 ℃ for 3 h and then filtered to give the title compound (3.00 g) .

Step 3: diethyl 7-benzyl-3, 4-dihydro-2H- [1, 4] dioxepino [2, 3-c] pyrrole-6, 8-dicarboxylate

To a stirred solution of diethyl 1-benzyl-3, 4-dihydroxy-pyrrole-2, 5-dicarboxylate (3.00 g, 9.0 mmol, 1.0 eq) and 1, 3-dibromopropane (2.00 g, 9.9 mmol, 1.1 eq) in DMF (60 mL) was added K₂CO₃ (3.11 g, 22.50 mmol, 2.5 eq) at room temperature under N₂. The reaction mixture was stirred at 105℃ for 12 h, then cooled to 20 ℃ and water was added. The resulting mixture was filtered and the solid cake was dried in vacuo to give the title compound (3.00 g) .

Step 4: 7-benzyl-3, 4-dihydro-2H- [1, 4] dioxepino [2, 3-c] pyrrole-6, 8-dicarboxylic acid

To a stirred solution of diethyl 7-benzyl-3, 4-dihydro-2H- [1, 4] dioxepino [2, 3-c] pyrrole-6, 8-dicarboxylate (3.00 g, 8.0 mmol, 1.0 eq) in EtOH (40 mL) and H₂O (8 mL) was added KOH (1.35 g, 24.1 mmol, 3.0 eq) . The reaction mixture was stirred at 90 ℃ for 12 h, cooled to 0 ℃, and then quenched with HCl aq. solution (10 mL, 1.0 M) at 0 ℃. The mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na₂SO₄, filtered and then concentrated to give the title compound (3.00 g, crude) , which was used in the next step without further purification.

Step 5: 7-benzyl-3, 4-dihydro-2H- [1, 4] dioxepino [2, 3-c] pyrrole

A mixture of 7-benzyl-3, 4-dihydro-2H- [1, 4] dioxepino [2, 3-c] pyrrole-6, 8-dicarboxylic acid (3.00 g, 9.45 mmol, 1.00 eq) and 2- [bis (2-hydroxyethyl) amino] ethanol (15 mL) was stirred at 180 ℃for 0.5 h. The reaction mixture was cooled to 20 ℃, quenched with water and then extracted with EtOAc. The combined organic layers were dried over anhydrous Na₂SO₄, filtered and then concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (5-10%) , to give the title compound (500 mg) .

Step 6: 2, 3, 4, 5a, 6, 7, 8, 8a-octahydro- [1, 4] dioxepino [2, 3-c] pyrrole

To a stirred solution of 7-benzyl-3, 4-dihydro-2H- [1, 4] dioxepino [2, 3-c] pyrrole (500 mg, 2.18 mmol, 1.00 eq) in MeOH (2 mL) were added AcOH (130 mg, 2.18 mmol, 1.00 eq) and 10%Pd/C (250 mg) at room temperature. The reaction mixture was stirred at 80 ℃ for 12 h under H₂ (50 psi) . The reaction mixture was filtered and then concentrated to give the title compound (400 mg, crude) as a yellow oil, which was used in the next step without further purification. MS (ES, m/z) : [M+H] ⁺=144.0.

Intermediate 6

Synthesis of a mixture of (5aR, 8aR) -hexahydro-2H, 6H- [1, 4] dioxepino [2, 3-c] pyrrole and (5aS, 8aS) -hexahydro-2H, 6H- [1, 4] dioxepino [2, 3-c] pyrrole

Step 1: benzyl 6-oxa-3-azabicyclo [3.1.0] hexane-3-carboxylate

To a stirred solution of benzyl 2, 5-dihydropyrrole-1-carboxylate (5.00 g, 24.6 mmol, 1.0 eq) in DCM (20 mL) was added m-CPBA (5.99 g, 29.5 mmol, 85%purity, 1.2 eq) at 20 ℃. The reaction mixture was stirred at 20 ℃ for 12 h, quenched with saturated aq. Na₂SO₃ (100 mL) , and then extracted with EtOAc. The combined organic layers were dried over anhydrous Na₂SO₄, filtered and then concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (25-50%) , to give the title compound (3.70 g) .

Step 2: mixture of benzyl (3R, 4R) -3- (3-bromopropoxy) -4-hydroxypyrrolidine-1-carboxylate and benzyl (3S, 4S) -3- (3-bromopropoxy) -4-hydroxypyrrolidine-1-carboxylate

To a stirred solution of benzyl 6-oxa-3-azabicyclo [3.1.0] hexane-3-carboxylate (3.30 g, 15.1 mmol, 1.0 eq) and 3-bromopropan-1-ol (2.30 g, 16.5 mmol, 1.1 eq) in DCM (60 mL) was added BF₃·Et₂O (213 mg, 1.51 mmol, 0.1 eq) . The reaction mixture was stirred at 20 ℃ for 5 h, concentrated and then purified by silica gel column chromatography, eluted with EA/PE (25-50%) , to give the title compound (2.40 g) .

Step 3: mixture of benzyl (5aR, 8aR) -hexahydro-2H, 7H- [1, 4] dioxepino [2, 3-c] pyrrole-7-carboxylate and benzyl (5aS, 8aS) -hexahydro-2H, 7H- [1, 4] dioxepino [2, 3-c] pyrrole-7-carboxylate

To a stirred solution of benzyl (3R, 4R) -3- (3-bromopropoxy) -4-hydroxypyrrolidine-1-carboxylate and benzyl (3S, 4S) -3- (3-bromopropoxy) -4-hydroxypyrrolidine-1-carboxylate (2.40 g, 6.70 mmol, 1.00 eq) in EtOH (50 mL) was added a solution of KOH (375 mg, 6.70 mmol, 1.00 eq) in EtOH (50 mL) . The reaction mixture was stirred at 85 ℃ for 0.5 h. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography, eluted with EA/PE (15-25%) , to give the title compound (900 mg) .

Step 4: mixture of (5aR, 8aR) -hexahydro-2H, 6H- [1, 4] dioxepino [2, 3-c] pyrrole and (5aS, 8aS) -hexahydro-2H, 6H- [1, 4] dioxepino [2, 3-c] pyrrole

To a stirred solution of benzyl (5aR, 8aR) -hexahydro-2H, 7H- [1, 4] dioxepino [2, 3-c] pyrrole-7-carboxylate and benzyl (5aS, 8aS) -hexahydro-2H, 7H- [1, 4] dioxepino [2, 3-c] pyrrole-7-carboxylate (500 mg, 1.80 mmol, 1.00 eq) in MeOH (2 mL) was added AcOH (130 mg, 2.18 mmol, 1.21 eq) and 10%Pd/C (250 mg) . The reaction mixture was stirred at 80 ℃ for 12 h under H₂ (50 psi) , cooled and then filtered. The filtrate was concentrated to give the title compounds (400 mg, crude) , which was used in the next step without further purification.

Intermediate 7

Synthesis of (4aS, 7aS) -hexahydro-5H- [1, 4] dioxino [2, 3-c] pyrrole and (4aR, 7aR) -hexahydro-5H- [1, 4] dioxino [2, 3-c] pyrrole

Step 1: a mixture of benzyl (3S, 4S) -3- (2-bromoethoxy) -4-hydroxypyrrolidine-1-carboxylate and benzyl (3R, 4R) -3- (2-bromoethoxy) -4-hydroxypyrrolidine-1-carboxylate

To a stirred solution of benzyl 6-oxa-3-azabicyclo [3.1.0] hexane-3-carboxylate (3.00 g, 13.7 mmol, 1.00 eq) , 2-bromoethanol (1.88 g, 15.1 mmol, 1.10 eq) in DCM (30 mL) was added dropwise BF₃·Et₂O (194 mg, 1.37 mmol, 0.10 eq) at 20 ℃. After stirring at 20℃ for 12 h, the reaction mixture was washed with brine, dried over Na₂SO₄, filtered and then concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (25-50%) , to provide a mixture of the title compounds (1.1 g) .

Step 2: benzyl (4aS, 7aS) -hexahydro-6H- [1, 4] dioxino [2, 3-c] pyrrole-6-carboxylate and benzyl (4aR, 7aS) -hexahydro-6H- [1, 4] dioxino [2, 3-c] pyrrole-6-carboxylate

To a stirred solution of benzyl (3S, 4S) -3- (2-bromoethoxy) -4-hydroxypyrrolidine-1-carboxylate and benzyl (3R, 4R) -3- (2-bromoethoxy) -4-hydroxypyrrolidine-1-carboxylate (800 mg, 2.32 mmol, 1.00 eq) in EtOH (8.0 mL) was added dropwise KOH (143 mg, 2.56 mmol, 1.10 eq) . The resulting mixture was stirred at 80 ℃ for 6 h, cooled and then filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography eluted with EA/PE (20-25%) . The product was further purified by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um) ; mobile phase: [CO₂-EtOH (0.1%NH₃H₂O) ] ; B%: 25%, isocratic elution mode) to give each of the title compounds.

Step 4: (4aS, 7aS) -hexahydro-5H- [1, 4] dioxino [2, 3-c] pyrrole and (4aR, 7aR) -hexahydro-5H- [1, 4] dioxino [2, 3-c] pyrrole

To a stirred solution of benzyl (4aS, 7aS) -hexahydro-6H- [1, 4] dioxino [2, 3-c] pyrrole-6-carboxylate or benzyl (4aR, 7aR) -hexahydro-6H- [1, 4] dioxino [2, 3-c] pyrrole-6-carboxylate (140 mg, 531.74 μmol, 1.00 eq) in THF (5 mL) was added Pd/C (10%, 0.05 g) under N₂. The reaction mixture was degassed and purged with H₂ for 3 times. The reaction mixture was stirred under H₂ (15 Psi) at 20℃ for 12 h and then filtered, and then concentrated to give (4aS, 7aS) -hexahydro-5H- [1, 4] dioxino [2, 3-c] pyrrole or (4aR, 7aR) -hexahydro-5H- [1, 4] dioxino [2, 3-c] pyrrole, respectively.

Intermediate 8

Synthesis of 4, 4-difluoro-2-oxa-8-azaspiro [4.5] decane

Step 1: tert-butyl 4, 4-difluoro-2-oxa-8-azaspiro [4.5] decane-8-carboxylate

To a solution of tert-butyl 4-oxo-2-oxa-8-azaspiro [4.5] decane-8-carboxylate (150 mg, 0.59 mmol) in DCM (3 mL) was added 2-methoxy-N- (2-methoxyethyl) -1- (trifluoro-lamda4-sulfanyl) ethan-1-amine (520 mg, 2.36 mmol) and the resulting mixture was stirred at 50 ℃ for 4 h. The reaction mixture was quenched with H₂O and extracted with EtOAc. The organic phases were combined, dried over Na₂SO₄, and concentrated to give the title compound (130 mg) .

Step 2: 4, 4-difluoro-2-oxa-8-azaspiro [4.5] decane

To a solution of tert-butyl 4, 4-difluoro-2-oxa-8-azaspiro [4.5] decane-8-carboxylate (130mg, 0.47 mmol) in anhydrous DCM (2 mL) was added HCl/Dioxane (1 mL, 4 M) at 0 ℃ and the resulting mixture was stirred at 25 ℃ for 1 h. The reaction mixture was then concentrated to provide the title compound.

Intermediate 9

Synthesis of 5-methoxy-5-methyloctahydrocyclopenta [c] pyrrole

Step 1: tert-butyl 5-hydroxy-5-methylhexahydrocyclopenta [c] pyrrole-2 (1H) -carboxylate

To a solution of tert-butyl 5-oxohexahydrocyclopenta [c] pyrrole-2 (1H) -carboxylate (1.60 g, 7.10 mmol, 1.00 eq) in toluene (20 mL) was added MeMgBr (3 M, 4.73 mL, 2.00 eq) at -30℃ and the resulting mixture was stirred at -30 ℃ for 2 h. The reaction mixture was quenched by sat. aq. NH₄Cl and then extracted with EtOAc. The combined organic layers were washed with H₂O and brine, dried over Na₂SO₄ and concentrated. The residue was purified by flash column chromatography eluted with EA/PE (20-50%) to give the title compound (1.80 g) .

Step 2: tert-butyl 5-methoxy-5-methylhexahydrocyclopenta [c] pyrrole-2 (1H) -carboxylate

To a solution of tert-butyl 5-hydroxy-5-methylhexahydrocyclopenta [c] pyrrole-2 (1H) -carboxylate (0.30 g, 1.24 mmol, 1.00 eq) in THF (5 mL) was added NaH (99.4 mg, 2.49 mmol, 60%purity, 2.00 eq) dropwise at 0 ℃ and the resulting mixture was stirred at at 0 ℃ for 1 h. MeI (353 mg, 2.49 mmol, 0.155 mL, 2.00 eq) was then added dropwise at 0 ℃ and the resulting mixture was stirred at 20 ℃ for 4 h. The reaction mixture was quenched by sat. aq. NH₄Cl at 0 ℃ and then extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated to give the title compound (0.30 g) .

Step 3: 5-methoxy-5-methyloctahydrocyclopenta [c] pyrrole

To a solution of tert-butyl 5-methoxy-5-methylhexahydrocyclopenta [c] pyrrole-2 (1H) -carboxylate (0.30 g, 1.17 mmol, 1.00 eq) in dioxane (1 mL) was added HCl/dioxane (4 M, 4 mL) and the resulting mixture was stirred at 20 ℃ for 2 h. The reaction mixture was concentrated to give the title compound (0.30 g) .

Intermediate 10

Synthesis of 1, 4-dioxa-9-azaspiro [5.5] undecane

Step 1: benzyl 4- ( (2-bromoethoxy) methyl) -4-hydroxypiperidine-1-carboxylate

To a solution of benzyl 1-oxa-6-azaspiro [2.5] octane-6-carboxylate (243 mg, 984 μmol, 1 eq) , 2-bromoethanol (123 mg, 983 μmol, 69.7 μL, 1.00 eq) in DCM (5 mL) was added BF₃. Et₂O (14.0 mg, 98.4 μmol, 12.1 μL, 0.1 eq) at 0 ℃ and the resulting mixture was stirred at 0 ℃ for 2 h. The reaction mixture was washed with H₂O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column flash chromatography eluted with EA/PE (5-10%) to give the title compound (70 mg) .

Step 2: benzyl 1, 4-dioxa-9-azaspiro [5.5] undecane-9-carboxylate

To a solution of benzyl 4- (2-bromoethoxymethyl) -4-hydroxy-piperidine-1-carboxylate (100 mg, 268 μmol, 1 eq) in THF (3 mL) was added t-BuOK (1 M, 268 μL, 1 eq) and the resulting mixture was stirred at 20 ℃ for 2 h. The reaction mixture was quenched by sat. aq. NH₄Cl and then extracted with EtOAc. The combined organic layers were concentrated and the residue was purified by silica gel column flash chromatography eluted with EA/PE (10-50%) to give the title compound (70.0 mg) .

Step 3: 1, 4-dioxa-9-azaspiro [5.5] undecane

A mixture of benzyl 1, 4-dioxa-9-azaspiro [5.5] undecane-9-carboxylate (70 mg, 240.27 μmol, 1 eq) and Pd/C (365.28 mg, 10%) in MeOH (5 mL) was stirred at 20 ℃ for 12 h under H₂ atmosphere (15 psi) . The reaction mixture was filtered and the filtrate was concentrated to provide the title compound (40 mg) .

Intermediate 11

Synthesis of 2- (8-ethynyl-7-fluoronaphthalen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane

Step 1: 2- (8-ethynyl-7-fluoronaphthalen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane

To a solution of ( (2- (2-fluoro-8- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) tris (propan-2-yl) silane (500 mg, 1.11 mmol) in DMF (5 mL) was added cesium fluoride (843.05 mg, 5.55 mmol) and the resulting mixture was stirred at 50 ℃ for 2 h under N₂. The reaction mixture was cooled at rt, then filtered and concentrated. The residue was purified by silica gel column chromatography eluted with EA/PE (0-100%) to give the title compound (300 mg) .

Intermediate 12

Synthesis of ( (3S, 7aS) -7a- (hydroxymethyl) -6-methylenehexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate

Step 1: methyl (5S, 7aR) -5- (hydroxymethyl) -2-methylenetetrahydro-1H-pyrrolizine-7a (5H) -carboxylate

To a stirred solution of methyl (5S, 7aS) -5- ( ( (tert-butyldiphenylsilyl) oxy) methyl) -2-methylenetetrahydro-1H-pyrrolizine-7a (5H) -carboxylate (5 g, 11.11 mmol, 1.0 equiv) in THF (50 mL) was added 1M TBAF in THF (16.6 mL, 16.6 mmol, 1.5 equiv) dropwise at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with THF/PE (0-50%) to afford the title compound (2.1 g, 89.36%) as a colorless oil.

Step 2: ( (3S, 7aS) -7a- (methoxycarbonyl) -6-methylenehexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate

To a stirred solution of methyl (5S, 7aR) -5- (hydroxymethyl) -2-methylenetetrahydro-1H-pyrrolizine-7a (5H) -carboxylate (2.1 g, 9.95 mmol, 1.0 equiv) and TEA (6.0 g, 59.7 mmol, 6.0 equiv) in THF (100 mL) was added 4-nitrophenyl carbonochloridate (10.0 g, 49.75 mmol, 5.0 equiv) in portions at 0-5 ℃. The resulting mixture was stirred 2 h at room temperature. To the above mixture was added morpholine (4.33 g, 49.75 mmol, 5.0 equiv) dropwise at 0-5 ℃. The resulting mixture was stirred for additional 16 h at room temperature. The resulting mixture was diluted with water. The resulting mixture was extracted with EA. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-100%) to afford the title compound (2.25 g, 69.8 %) as yellow oil.

Step 3: ( (3S, 7aS) -7a- (hydroxymethyl) -6-methylenehexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate

To a stirred solution of ( (3S, 7aS) -7a- (methoxycarbonyl) -6-methylenehexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate (2.25 g, 7.58 mmol, 1.0 equiv) and CaCl₂ (2.1 g, 18.9 mmol, 2.5 equiv) in EtOH (24 mL) and H₂O (6 mL) was added NaBH₄ (1.54 g, 40.9 mmol, 5.4 equiv) in portions at 0 ℃. The resulting mixture was stirred for 1 h at 0 -5℃. The reaction was quenched with water at 0 ℃. The resulting mixture was extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (1.7 g, 82.5%) as a yellow oil. MS (ES, m/z) : [M+H] ⁺=297.1.

Example 1

Synthesis of ( (3S, 7aS) -7a- ( ( (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) -6-methylenehexahydro-1H-pyrrolizin-3-yl) methyl 6-oxa-2-azaspiro [3.4] octane-2-carboxylate

Step 1: tert-butyl 3- [2- [ [ (3S, 8S) -3- [ [tert-butyl (diphenyl) silyl] oxymethyl] -6-methylene-2, 3, 5, 7-tetrahydro-1H pyrrolizin-8-yl] methoxy] -7- (8-ethynyl-7-fluoro-1-naphthyl) -8-fluoro-pyrido [4, 3-d] pyrimidin-4-yl] -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

To a solution of tert-butyl 3- [2-chloro-7- (8-ethynyl-7-fluoro-1-naphthyl) -8-fluoro-pyrido [4, 3-d] pyrimidin-4-yl] -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (900 mg, 1.60 mmol, 1 eq) and [ (3S, 8S) -3- [ [tert-butyl (diphenyl) silyl] oxymethyl] -6-methylene-2, 3, 5, 7-tetrahydro-1H-pyrrolizin-8-yl] methanol (742 mg, 1.76 mmol, 1.1 eq) in THF (20 mL) was added NaH (160 mg, 4.00 mmol, 60%purity, 2.5 eq) at 0 ℃ slowly. The mixture was stirred at 20 ℃ for 2 h under N₂. The mixture was quenched by addition aq. NH₄Cl 10 mL at 0 ℃, and then extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography, eluted with EA/PE (0-30%) to afford the title compound (1.00 g) .

Step 2: tert-butyl 3- [7- (8-ethynyl-7-fluoro-1-naphthyl) -8-fluoro-2- [ [ (3S, 8S) -3- (hydroxymethyl) -6-methylene-2, 3, 5, 7-tetrahydro-1H-pyrrolizin-8-yl] methoxy] pyrido [4, 3-d] pyrimidin-4-yl] -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

To a solution of tert-butyl 3- [2- [ [ (3S, 8S) -3- [ [tert-butyl (diphenyl) silyl] oxymethyl] -6-methylene-2, 3, 5, 7-tetrahydro-1H-pyrrolizin-8-yl] methoxy] -7- (8-ethynyl-7-fluoro-1-naphthyl) -8-fluoro-pyrido [4, 3-d] pyrimidin-4-yl] -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (450 mg, 475 umol, 1 eq) in THF (5 mL) was added TBAF (1 M, 2.38 mL, 5 eq) and AcOH (142 mg, 2.38 mmol, 135 uL, 5 eq) . The mixture was stirred at 40 ℃ for 4 h under N₂. The mixture was quenched with water and then extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography eluted with EA/PE (0-10%) to afford the title compound (650 mg) .

Step 3: ( (3S, 7aS) -7a- ( ( (4- ( (1R, 5S) -8- (tert-butoxycarbonyl) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) -6- methylenehexahydro-1H-pyrrolizin-3-yl) methyl6-oxa-2-azaspiro [3.4] octane-2-carboxylate

To a solution of tert-butyl (1R, 5S) -3- (7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ( ( (5S, 7aS) -5- (hydroxymethyl) -2-methylenetetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (100 mg, 141.1 umol) in THF (1 mL) was added TEA (142.5 mg, 1410.8 umol, 10 eq. ) and (4-nitrophenyl) carbonochloridate (142.2 mg, 705.4 umol, 5 eq) . After stirring at 25 ℃ for 3 h., 6-oxa-2-azaspiro [3.4] octane oxalic acid (223.6mg, 705.4 umol, 5 eq. ) was added and the resulting mixture was stirred at 25 ℃ for 2 hrs. The reaction mixture was quenched by addition sat. NahCO₃ aq. solution and then extracted with EtOAc. The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by column chromatography, eluted with PE/EA (0-40%) to DCM/MeOH (0-4%) to afford the title compound (110 mg) .

Step 3: ( (3S, 7aS) -7a- ( ( (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) -6-methyl enehexahydro-1H-pyrrolizin-3-yl) methyl 6-oxa-2-azaspiro [3.4] octane-2-carboxylate

To a solution of ( (3S, 7aS) -7a- ( ( (4- ( (1R, 5S) -8- (tert-butoxycarbonyl) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) -6-methylenehexahydro-1H-pyrrolizin-3-yl) methyl 6-oxa-2-azaspiro [3.4] octane-2-carboxylate (110 mg, 129.7 umol) in DCM (1 mL) was added TFA (0.4 mL) at 5 ℃ and the mixture was stirred at rt for 1 h. The reaction mixture was basified to pH = 8 by adding a solution of NH₃ in MeOH and then concentrated. The residue was purified by Prep-HPLC, to afford the title compound (43.52 mg) . MS (ES, m/z) : [M+H] ⁺ =748.3.

Proceeding analogously as described in Example 1, Steps 3 and 4, compounds in Table below were prepared by replacing 6-oxa-2-azaspiro [3.4] octane in Step 3, with amines indicated therein.

Example 2

Synthesis of 4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ( ( (5S, 7aS) -2-methylene-5- ( (pyrimidin-4-yloxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidine

Step 1: methyl (5S, 7aS) -2-methylene-5- ( (pyrimidin-4-yloxy) methyl) tetrahydro-1H-pyrrolizine-7a (5H) -carboxylate

To a stirred solution of methyl (5S, 7aS) -5- (hydroxymethyl) -2-methylenetetrahydro-1H-pyrrolizine-7a (5H) -carboxylate (200 mg, 0.9 mmol, 1.0 equiv) and 4-chloropyrimidine (108 mg, 0.9 mmol, 1.0 equiv) in THF (4 mL) was added NaH (76 mg, 1.9 mmol, 2.0 equiv, 60%) at rt under nitrogen atmosphere and the resulting mixture was stirred for 2 h at rt. The reaction mixture was quenched by adding sat. NH₄Cl aq. solution and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluted with THF /PE (0-30%) to afford the title compound (100 mg) .

Step 2: ( (5S, 7aS) -2-methylene-5- ( (pyrimidin-4-yloxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol

To a stirred solution of methyl (5S, 7aS) -2-methylene-5- ( (pyrimidin-4-yloxy) methyl) tetrahydro-1H-pyrrolizine-7a (5H) -carboxylate (100 mg, 0.35 mmol, 1.0 equiv) in THF (3 mL) at 0 ℃ was added LiAlH₄ (1.0 M in THF, 0.5 mL, 0.5 mmol, 1.5 equiv) and the resulting mixture was stirred at 0 ℃ for 1 h. The mixture was quenched by adding 15%NaOH aq. solution and Na₂SO₄ was added. The resulting mixture was filtered, and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to provide the title compound (70 mg) .

Step 3: tert-butyl (1R, 5S) -3- (7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ( ( (5S, 7aS) -2-methylene-5- ( (pyrimidin-4-yloxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

To a stirred solution of tert-butyl (1R, 5S) -3- (2-chloro-7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (45 mg, 0.08 mmol, 1.0 equiv) and ( (5S, 7aS) -2-methylene-5- ( (pyrimidin-4-yloxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (21 mg, 0.08 mmol, 1.0 equiv) in THF (2 mL) at 0 ℃ was added NaH (6 mg, 60%in mineral oil, 0.16 mmol, 2 equiv) and the resulting mixture was stirred at 0 ℃ for 1 h. The resulting mixture was quenched by adding sat. NH₄Cl aq. solution and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluted with THF /PE (0-35%) to afford the title compound (35 mg) .

Step 4: 4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ( ( (5S, 7aS) -2-methylene-5- ( (pyrimidin-4-yloxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidine

To a solution of tert-butyl (1R, 5S) -3- (7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ( ( (5S, 7aS) -2-methylene-5- ( (pyrimidin-4-yloxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (30 mg, 0.04 mmol, 1 equiv) in DCM (0.3 mL) at 0 ℃. was added HCl solution in 1, 4-dioxane (4.0 M, 0.15 mL) and the resulting mixture was stirred for 1 h at 0 ℃. The reaction mixture was basified to pH=8 by adding a solution of ammonia in MeOH and then concentrated under reduced pressure. The residue was purified by Prep-HPLC to afford the title compound (2.6 mg) . MS (ES, m/z) : [M+H] ⁺=687.4.

Example 3

Synthesis of 4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ( ( (5S, 7aS) -2-methylene-5- ( (pyrimidin-2-yloxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidine

The title compound was synthesized analogously as described in Example 2, steps 1-4 using 2-chloropyrimidine instead of 4-chloropyrimidine in step 1. MS (ES, m/z) : [M+H] ⁺=687.4.

Example 4

Synthesis of 4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ( ( (5S, 7aS) -2-methylene-5- ( (pyridin-2-yloxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidine

Step 1: methyl (5S, 7aS) -2-methylene-5- ( (pyridin-2-yloxy) methyl) tetrahydro-1H-pyrrolizine-7a (5H) -carboxylate

To a stirred solution of methyl (1R, 3aR) -1- (hydroxymethyl) -5-methylenehexahydropentalene-3a (1H) -carboxylate (210 mg, 0.99 mmol, 1.0 equiv) , PPh₃ (390 mg, 1.49 mmol, 1.5 equiv) and 2-pyridone (142 mg, 1.49 mmol, 1.5 equiv) in THF (1 mL) at 0 ℃ was added DIAD (300 mg, 1.49 mmol, 1.5 equiv) and the resulting mixture was stirred for 2 h at rt. The reaction mixture was diluted with water and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography, eluted with EtOAc/PE (0-20%) to afford the title compound (100 mg) .

Step 2: 4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2- ( ( (5S, 7aS) -2-methylene-5- ( (pyridin-2-yloxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidine

The title compound was synthesized analogously as described in Example 2, step 2-4 using methyl (5S, 7aS) -2-methylene-5- ( (pyridin-2-yloxy) methyl) tetrahydro-1H-pyrrolizine-7a (5H) -carboxylate instead of methyl (5S, 7aS) -2-methylene-5- ( (pyrimidin-4-yloxy) methyl) tetrahydro-1H-pyrrolizine-7a (5H) -carboxylate in step 2. MS (ES, m/z) : [M+H] ⁺=686.4.

Example 5

The title compound was synthesized analogously as described in Example 4, steps 1-2 using 1-methylpyrazol-3-ol instead of 2-pyridone in step 1. MS (ES, m/z) : [M+H] ⁺=689.4.

Example 6

Compound 58

Synthesis of ( (3S, 7aS) -7a- ( ( (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-5-methoxypyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) -6-methylenehexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate

Step 1: 7-chloro-8-fluoro-5-methoxy-2- (methylthio) pyrido [4, 3-d] pyrimidin-4 (3H) -one

To a solution of 5, 7-dichloro-8-fluoro-2- (methylsulfanyl) -3H, 4H-pyrido [4, 3-d] pyrimidin-4-one (2.00 g, 7.14 mmol) in anhydrous DMF (10 mL) was added sodium methoxide (1.01 g, 18.56 mmol) and the resulting mixture was stirred at 25 ℃ for 16 h. The reaction mixture was cooled at 0 ℃ and acidified to pH～3 with conc. HCl. The mixture was then was filtered, and the filter cake was washed with brine, dried, and triturated in methanol to afford the title compound (1.86 g) .

Step 2: tert-butyl (1R, 5S) -3- (7-chloro-8-fluoro-5-methoxy-2- (methylthio) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

To a solution of 7-chloro-8-fluoro-5-methoxy-2- (methylsulfanyl) -3H, 4H-pyrido [4, 3-d] pyrimidin-4-one (500.00 mg, 1.81 mmol) in CH₃CN (3 mL) were added POCl₃ (333.03 mg, 2.17 mmol) and DIPEA (701.77 mg, 5.43 mmol) . The mixture was stirred at 80 ℃ for 1 h under N₂ and then cooled to 0 ℃. Tert-butyl (1R, 5S) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (384.24 mg, 1.81 mmol) was added and the mixture was stirred for 1 h at 25 ℃. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography eluted with MeOH/DCM (0-10%) to give the title compound (543.00 mg) .

Step 3: tert-butyl 3- (7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-5-methoxy-2- (methylthio) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

To a solution of tert-butyl (1R, 5S) -3- (7-chloro-8-fluoro-5-methoxy-2- (methylsulfanyl) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (500.00 mg, 1.06 mmol) in dioxane (2 mL) and H₂O (0.4 mL) were added 2- (8-ethynyl-7-fluoronaphthalen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (627.82 mg, 2.12 mmol) , K₂CO₃ (439.51 mg, 3.18 mmol) and tetrakis (triphenylphosphine) palladium (122.49 mg, 0.11 mmol) . The mixture was then stirred at 85 ℃ for 16 h under N₂. After cooled at rt, the reaction mixture was diluted with EtOAc, washed with sat. aq. NaHCO₃ and brine successively. The combined organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography eluted with EA/PE (0%-100%) to give the title compound (100.00 mg) .

Step 4: tert-butyl 3- (7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-5-methoxy-2- (methylsulfonyl) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate

To a solution of (tert-butyl (1R, 5S) -3- (7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-5-methoxy-2- (methylsulfanyl) pyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (45.00 mg, 0.075 mmol) in anhydrous DCM (2 mL) was added mCPBA (25.89 mg, 0.15 mmol) at 0 ℃ and the resulting mixture was stirred at 25 ℃ for 2 h. The reaction mixture was diluted with EA and then washed with saturated aqueous NaHCO₃ and brine successively. The organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography eluted with EA/PE (0-100%) to give the title compound.

Step 5: ( (3S, 7aS) -7a- ( ( (4- ( (1R, 5S) -8- (tert-butoxycarbonyl) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-5-methoxypyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) -6-methylenehexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate

To a solution of tert-butyl 3- (7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-2-methanesulfonyl-5-methoxypyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (15 mg, 0.024 mmol) in toluene (0.5 mL) were added [ (3S, 7aS) -7a- (hydroxymethyl) -6-methylidene-hexahydro-1H-pyrrolizin-3-yl] methyl morpholine-4-carboxylate (8.54 mg, 0.029 mmol) and potassium tert-butoxide (4.61 mg, 0.05 mmol) and the resulting mixture was stirred at 25 ℃ for 16 h. The mixture was concentrated and the residue was purified by silica gel column chromatography eluted with EA/PE (0-20%) to give the title compound (10.00 mg) .

Step 6: ( (3S, 7aR) -7a- ( ( (4- (3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-5-methoxypyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) -6-methylenehexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate

To a solution of tert-butyl tert-butyl 3- (2- { [ (5S, 7aS) -2-methylidene-5- [ (morpholine-4-carbonyloxy) methyl] -hexahydro-1H-pyrrolizin-7a-yl] methoxy} -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoro-5-methoxypyrido [4, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (10.00 mg, 0.01 mmol) in DCM (2 mL) was added HCl/Dioxane (1.5 mL, 4 M) at 0 ℃ and the resulting mixture was stirred at 25 ℃ for 1 h. The reaction mixture was concentrated and the residue was diluted with DCM and basified with NH₃/MeOH (0.5 mL, 7 M) at 0 ℃. The resulting mixture was concentrated and the residue was purified by Prep-TLC [DCM: (NH₃/MeOH, 2 M) =10: 1] to give the title compound (2.00 mg) . MS (ES, m/z) : [M+H] ⁺=752.

Example 7

Compound 74

Synthesis of 2- ( (3S, 7aS) -7a- ( ( (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) -6-methylenehexahydro-1H-pyrrolizin-3-yl) ethyl 3, 3-difluoropyrrolidine-1-carboxylate

The title compound was prepared by proceeding analogously as described in Example 1, step 1-3, using ( (5S, 7aR) -5- (2- ( (tert-butyldiphenylsilyl) oxy) ethyl) -2-methylenetetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol instead of [ (3S, 8S) -3- [ [tert-butyl (diphenyl) silyl] oxymethyl] -6-methylene-2, 3, 5, 7- tetrahydro-1H-pyrrolizin-8-yl] methanol in step 1, and 3, 3-difluoropyrrolidine hydrogen chloride instead of 6-oxa-2-azaspiro [3.4] octane oxalic acid in step 2. MS (ES, m/z) : [M+H] ⁺=756.4.

Example 8

Compound 73

Synthesis of 2- ( (3S, 7aS) -7a- ( ( (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoronaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) -6-methylenehexahydro-1H-pyrrolizin-3-yl) ethyl morpholine-4-carboxylate

The title compound was prepared by proceeding analogously as described in Example 1, step 1-3, using ( (5S, 7aR) -5- (2- ( (tert-butyldiphenylsilyl) oxy) ethyl) -2-methylenetetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol instead of [ (3S, 8S) -3- [ [tert-butyl (diphenyl) silyl] oxymethyl] -6-methylene-2, 3, 5, 7-tetrahydro-1H-pyrrolizin-8-yl] methanol in step 1, and 3, 3-difluoropyrrolidine hydrogen chloride instead of 6-oxa-2-azaspiro [3.4] octane oxalic acid in step 2. MS (ES, m/z) : [M+H] ⁺=736.4.

Example 9

Compound 75

Synthsis of ( (3S, 7aS) -7a- ( ( (7- (3-amino-8-ethynyl-7-fluoronaphthalen-1-yl) -4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) -6-methylenehexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate

Step 1: ( (3S, 7aS) -7a- ( ( (4- ( (1R, 5S) -8- (tert-butoxycarbonyl) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7-chloro-8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) -6-methylenehexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate

To a solution of tert-butyl 3- {2, 7-dichloro-8-fluoropyrido [4, 3-d] pyrimidin-4-yl} -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (300 mg, 0.7 mmol, 1.0 eq) and ( (3S, 7aS) -7a- (hydroxymethyl) -6-methylenehexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate (208 mg, 0.7 mmol, 1 eq) in THF (3 mL) was added NaH (56 mg, 1.4 mmol, 2 eq, 60%) at 0 ℃ under N₂, and the resulting mixture was stirred at rt for 30 mins. The reaction mixture was quenched with H₂O and extracted with DCM. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-100%) to afford the title compound (30 mg) .

Step 2: ( (3S, 7aS) -7a- ( ( (7- (3-amino-7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -4- ( (1R, 5S) -8- (tert-butoxycarbonyl) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) -6-methylenehexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate

To a solution of ( (3S, 7aS) -7a- ( ( (4- ( (1R, 5S) -8- (tert-butoxycarbonyl) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7-chloro-8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) -6-methylenehexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate (80 mg, 0.1 mmol, 1.0 eq) and 6-fluoro-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5- [2- (triisopropylsilyl) ethynyl] -naphthalen-2-amine (54 mg, 0.1 mmol, 1.0 eq) in DME (0.4 mL) and H₂O (0.1 mL) were added K₂CO₃ (48 mg, 0.3 mmol, 3.0 eq) and CATACXIUM A Pd G3 (8 mg, 0.01 mmol, 0.1 eq) . The reaction mixture was stirred at 85 ℃ at 3 h under N₂, after which it was cooled at rt and concentrated. The residue was purified by silica gel column chromatography, eluted with MeOH/DCM (0～10%) to afford the title compound (86 mg) .

Step 3: ( (3S, 7aS) -7a- ( ( (7- (3-amino-8-ethynyl-7-fluoronaphthalen-1-yl) -4- ( (1R, 5S) -8- (tert-butoxycarbonyl) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) -6-methylenehexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate

To a solution of tert-butyl ( (3S, 7aS) -7a- ( ( (7- (3-amino-7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -4- ( (1R, 5S) -8- (tert-butoxycarbonyl) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) -6-methylenehexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate (86 mg, 0.087 mmol, 1.0 eq) in DMF (1 mL) was added CsF (66 mg, 0.4 mmol, 5.0 eq) at rt. The reaction mixture was stirred at 60 ℃ for 3 h, after which it was cooled at rt, quenched with H₂O and then extracted with DCM. The combined organic extracts were washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with MeOH/DCM (0-10%) to afford the title compound (60 mg) .

Step 4: ( (3S, 7aS) -7a- ( ( (7- (3-amino-8-ethynyl-7-fluoronaphthalen-1-yl) -4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) -6-methylenehexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate

To a mixture of ( (3S, 7aS) -7a- ( ( (7- (3-amino-8-ethynyl-7-fluoronaphthalen-1-yl) -4- ( (1R, 5S) -8- (tert-butoxycarbonyl) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2- yl) oxy) methyl) -6-methylenehexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate (30 mg, 0.036 mmol, 1.0 eq) in DCM (0.6 mL) was added HCl solution in Dioxane (0.3 mL, 4.0 M) dropwise at 5 ℃. The resulting mixture was stirred at 5℃ for 2 hrs, after which it was basified to pH～8 with NH₃/MeOH at 5 ℃ and then concentrated. The residue was purified by Prep-HPLC to afford the title compound (6.9 mg) . MS (ES, m/z) : [M+H] ⁺=737.4.

Example 10

Compound 76

Synthsis of ( (3S, 7aS) -7a- ( ( (4- ( (1R, 5S) -3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoropyrido [4, 3-d] pyrimidin-2-yl) oxy) methyl) -6-methylenehexahydro-1H-pyrrolizin-3-yl) methyl morpholine-4-carboxylate

The title compound was prepared by proceeding analogously as described in Example 9, Steps 2-4, using ( (2-fluoro-6- (methoxymethoxy) -8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane instead of 6-fluoro-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5- [2- (triisopropylsilyl) ethynyl] naphthalen-2-amine in Step 2. MS (ES, m/z) : [M+H] ⁺=738.2.

In examples 16, 38-43, 45-48, 51-54, 63-72, 77, and 78 HCl/Dioxane (1 mL, 4 M) was used instead of TFA in Step 3 to remove the Boc protecting group.

Compounds 55 and 56 were synthesized as a mixture and then were separated by chiral SFC: column: REGIS (s, s) WHELK-O1 (250mm*30mm, 5um) ; mobile phase: [CO₂-ACN/EtOH (0.1%NH₃H₂O) ] ; B%: 50%, isocratic elution mode.

Biological Examples

Example 1

p-ERK Cellular 1-plate Assay

The ability of the compound of Formula (I) or a pharmaceutically acceptable salt thereof (test compound) to inhibit K-Ras G12D activity was tested using AGS (Cobioer, CBP60476) cell lines which harbor KRAS G12D mutation as described below.

AGS (Cobioer, CBP60476) were seeded in 384-well plates and cultured overnight (5,000 cells per well, 40 μl total volume) . The following morning, cells were treated with test compound, with starting concentration at 10 μM and 3-fold dilution down to 0.5 nM for 3 h at 37 ℃. DMSO treatment served as Control. p-ERK was then measured using AlphaLISA SureFire Ultra p-ERK1/2 (Thr202/Tyr204) Assay Kit (Perkin Elmer, cat# ALSU-PERK) following the manufacturer’s instruction as follows.

Briefly, the culture medium was removed and 10 μl 1× lysis buffer was added to each well, followed by 10 minutes incubation on a plate shaker at room temperature. Acceptor mixture was prepared according to manufacturer's instruction. 5 μl acceptor mixture was added to the cell lysate and the plate was wrapped with foil, spun at 500 rpm for 10s and incubated at RT for 60 min. Donor mixture was prepared under subdued light. 5 μl donor mixture was added to the cell lysate and the plate was spun at 500 rpm for 10s and incubated at RT for another 60 min. in the dark. Signal was then measured on a EnVision 2105 multimode plate reader. Percentage inhibition was calculated with DMSO treatment as 100%of signal, and EC₅₀ was calculated by XLfit 5.5. x.

EC₅₀ of compound in Compound Table 1 above are disclosed in Table A below

Table A

Formulation

Examples

The following are representative pharmaceutical formulations containing a compound of the present disclosure.

Tablet Formulation

The following ingredients are mixed intimately and pressed into single scored tablets.

Capsule Formulation

The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.

Injectable Formulation

Compound of the disclosure (e.g., compound 1) in 2%HPMC, 1%Tween 80 in DI water, pH 2.2 with MSA, q.s. to at least 20 mg/mL

Inhalation Composition

To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a compound disclosed herein is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9%sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration.

Topical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of a compound disclosed herein is mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then ncorporated into containers, such as tubes, which are suitable for topical administration.

Ophthalmic Solution Composition

To prepare a pharmaceutical ophthalmic solution composition, 100 mg of a compound disclosed herein is mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration.

Nasal spray solution

To prepare a pharmaceutical nasal spray solution, 10 g of a compound disclosed herein is mixed with 30 mL of a 0.05M phosphate buffer solution (pH 4.4) . The solution is placed in a nasal administrator designed to deliver 100 ul of spray for each application.

Claims

A compound of Formula (I) :

wherein:

U, V, and W are CH; or one or two of U, V, and W are N and the other of U, V, and W are CH;

R¹ is a ring of formula:

where:

one of m and n is 0, 1, or 2, and the other of m and n is 0, 1, 2, or 3;

R⁶ is hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, hydroxy, hydroxylalkyl, alkoxyalkyl, cyano, or cyanomethyl, provided R⁶ is not attached to the ring -NH-;

R⁷ is hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, hydroxy, hydroxylalkyl, or alkoxyalkyl, provided R⁷ is not attached to the ring -NH-; or

when R⁶ and R⁷ are attached to the carbon atoms of the ring that are opposite or diagonal to each other, then R⁶ and R⁷ can combine to form – (CH₂) _z-where (z is 1, 2, or 3) , or -CH=CH-;

R^6a is hydrogen, deuterium, alkyl, alkylidenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, cyanomethyl, cyanoethyl, or 2-cyanovinyl,

provided R^6a is not attached to the ring -NH-;

R^6b is hydrogen or alkyl, provided R^6b is not attached to the ring -NH-; or

when R^6a and R^6b are attached to the same carbon of ring (a’) , they can combine to form cycloalkylene;

R² is hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, or cyano, provided that R² is absent when two of U, V, and W are N;

R³ is hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, cycloalkyl, cycloalkyloxy, hydroxy, or cyano;

R⁴ is -Z-R³⁰ where Z is a bond, O, NH, N (alkyl) , or S; and R³⁰ is heterocyclylalkyl, fused heterocyclylalkyl, bicyclic heterocyclyl, bicyclic heterocyclylalkyl, fused bicyclic heterocyclyl, fused bicyclic heterocyclylalkyl, heterocyclyl fused bicyclic heterocyclyl, heterocyclyl fused bicyclic heterocyclylalkyl, tricyclic heterocyclyl, or tricyclic heterocyclylalkyl, wherein:

(1) fused heterocyclyl of fused heterocyclylalkyl is substituted with R^a, R^b, R^c, and R^c1 where R^a is alkylidenyl, deuterioalkylidenyl, haloalkylidenyl, alkoxyalkylidenyl, or =CR³¹R³² and the alkyl portion of fused heterocyclylalkyl is optionally substituted with one or two deuterium;

(2) heterocyclyl of heterocyclylalkyl and bicyclic heterocyclyl, by itself or as part of bicyclic heterocyclylalkyl, are substituted with R^d, R^e, R^f and R^f1 where R^d is alkylidenyl, deuterioalkylidenyl, haloalkylidenyl, alkoxyalkylidenyl, or =CR³³R³⁴ and the alkyl portion of heterocyclylalkyl, and bicyclic heterocyclylalkyl is optionally substituted with one or two deuterium;

(3) fused bicyclic heterocyclyl, by itself or as part of fused bicyclic heterocyclylalkyl, heterocyclyl fused bicyclic heterocyclyl, by itself or as part of heterocyclyl fused bicyclic heterocyclylalkyl, and tricyclic heterocyclyl, by itself or as part of tricyclic heterocyclylalkyl, are independently substituted with R^g, R^h, Rⁱ, and Rⁱ¹ where R^g alkylidenyl, deuterioalkylidenyl, haloalkylidenyl, alkoxyalkylidenyl, or =CR³⁵R³⁶ and the alkyl portion of fused bicyclic heterocyclylalkyl, heterocyclyl fused bicyclic heterocyclylalkyl, and tricyclic heterocyclylalkyl is optionally substituted with one or two deuterium;

R³¹, R³³, and R³⁵ are independently hydrogen, alkyl, or fluoro and R³², R³⁴, and R³⁶ are independently cyano, alkoxyalkyloxyalkyl, cycloalkyl, cycloalkylalkyl, or cycloalkylalkyloxyalkyl (where cycloalkyl, by itself or as part of cycloalkylalkyl and cycloalkylalkyloxyalkyl is optionally substituted with one or two substituents independently selected from alkyl, halo, haloalkoxy, alkoxy, alkoxyalkyl, and hydroxy) , heterocyclyl, phenyl, or heteroaryl (where heterocyclyl, phenyl, and heteroaryl are optionally substituted with one, two, or three substituents independently selected from alkyl, halo, haloalkyl, haloalkoxy, alkoxy, cyano, and hydroxy) , or independently of each other, R³¹ and R³², R³³ and R³⁴, and R³⁵ and R³⁶ together with the carbon atom to which they are attached form cycloalkylene optionally substituted with alkyl, halo, alkoxy, or hydroxy;

R^b, R^e, and R^h are – (Q¹) -OC (O) NR³⁹R⁴⁰ wherein:

(a) Q¹ is alkylene, R³⁹ is hydrogen, deuterium, alkyl, deuterioalkyl, haloalkyl, haloalkoxyalkyl, or alkoxyalkyl and R⁴⁰ is deuterium, deuterioalkyl, cycloalkyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, or heterocyclyl optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, haloalkyl, and haloalkoxy; or R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl wherein (a) the heterocyclyl formed together by R³⁹ and R⁴⁰ is substituted with Rⁿ, R^o, R^p, and R^q where Rⁿ and R^o are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, haloalkoxy, cyano, alkoxy and hydroxy, R^p is hydrogen, deuterium, alkylidene, deuterioalkylidene, alkenyl, alkynyl, fluoro, alkoxyalkyl, alkylcarbonyl, haloalkylcarbonyl, or alkylsulfonyl, and R^q is hydrogen, deuterium, or fluoro and (b) the bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiroheterocyclyl formed together by R³⁹ and R⁴⁰ are independently substituted with R^r, R^s, and R^t independently selected from hydrogen, deuterium, alkyl, alkylthio, halo, haloalkyl, haloalkoxy, cyano, alkoxy, and hydroxy; or

(b) Q¹ is deuterioalkylene, R³⁹ is hydrogen, deuterium, alkyl, deuterioalkyl, haloalkyl, haloalkoxyalkyl, or alkoxyalkyl and R⁴⁰ is hydrogen, deuterium, alkyl, deuterioalkyl, cycloalkyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, or heterocyclyl optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, haloalkyl, and haloalkoxy; or R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl wherein (a) heterocyclyl is substituted with R^u, R^v, R^w, and R^x where R^u and R^v are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, haloalkoxy, cyano, alkoxy and hydroxy, R^w is hydrogen, deuterium, alkylidene, deuterioalkylidene, alkenyl, alkynyl, fluoro, alkoxyalkyl, alkylcarbonyl, haloalkylcarbonyl, or alkylsulfonyl, and R^x is hydrogen, deuterium, or fluoro and (b) bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiroheterocyclyl are independently substituted with R^y, R^y1, and R^y2 independently selected from hydrogen, deuterium, alkyl, alkylthio, halo, haloalkyl, haloalkoxy, cyano, alkoxy, and hydroxy;

R^c, R^f, and Rⁱ are independently hydrogen, deuterium, alkyl, halo, alkoxy, alkoxyalkyl, or hydroxy;

R^c1, R^f1, and Rⁱ¹ are independently selected from hydrogen, deuterium, alkyl, and halo; and

R⁵ is -Q-R³⁷ where Q is a bond, alkylene, or -C (=O) -; and R³⁷ is cycloalkyl, fused cycloalkyl, fused spirocycloalkyl, aryl, aralkyl, heteroaryl, fused heteroaryl, or heteroaralkyl wherein aryl, aryl in aralkyl, heteroaryl, fused heteroaryl, and heteroaryl in heteroaralkyl are independently substituted with R^aa, R^bb, R^cc and R^dd wherein R^aa and R^bb are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R^cc is hydrogen, alkenyl, alkynyl, cyanoalkenyl, cyanoalkynyl, or halo, and R^dd is hydrogen, alkyl, alkylthio, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl; or

a pharmaceutically acceptable salt thereof; provided that when R^b, R^e, and R^h are – (Q¹) -OC (O) NR³⁹R⁴⁰ where Q¹ is alkylene and R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form heterocyclyl substituted with Rⁿ, R^o, R^p, and R^q; R^a, R^d, and R^g are not deuterioalkylidene; R⁴ is fused heterocyclylalkyl, heterocyclylalkyl, bicyclic heterocyclylalkyl, fused bicyclic heterocyclylalkyl, fused bicyclic heterocyclylalkyl, heterocyclyl fused bicyclic heterocyclylalkyl, and tricyclic heterocyclylalkyl wherein the alkyl portion of fused heterocyclylalkyl, heterocyclylalkyl, bicyclic heterocyclylalkyl, fused bicyclic heterocyclylalkyl, fused bicyclic heterocyclylalkyl, heterocyclyl fused bicyclic heterocyclylalkyl, and tricyclic heterocyclylalkyl is not substituted with one or two deuterium; R^c, R^f, and Rⁱ are not deuterium; and R^c1, R^f1, and Rⁱ¹ are hydrogen; then: (i) when R^p is fluoro, then Rⁿ and R^o are not hydrogen; and (ii) when R^p is hydrogen, then Rⁿ, R^o and R^q are not hydrogen.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, having a structure according to Formula (I’c) :
The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is heterocyclylalkyl, bicyclic heterocyclyl, or bicyclic heterocyclylalkyl, where heterocyclyl of heterocyclylalkyl and bicyclic heterocyclyl, by itself or as part of bicyclic heterocyclylalkyl are substituted with R^d, R^e, R^f, and R^f1.
The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is heterocyclylalkyl or bicyclic heterocyclylalkyl, where heterocyclyl of heterocyclylalkyl and bicyclic heterocyclyl of bicyclic heterocyclylalkyl are substituted with R^d, R^e, R^f, and R^f1 and alkyl of heterocyclylalkyl and bicyclic heterocyclylalkyl is substituted with one or two deuterium.
The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is heterocyclylalkyl where heterocyclyl of heterocyclylalkyl is substituted with R^d, R^e, R^f, and R^f1.
The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the heterocyclylalkyl of R³⁰ is pyrrolidin-2-ylmethyl, piperidin-2-ylmethyl, or piperidin-3-ylmethyl, each ring substituted with R^d, R^e, R^f, and R^f1.
The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein the heterocyclylalkyl of R³⁰ is pyrrolidin-2-ylmethyl substituted with R^d, R^e, R^f, and R^f1.
The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R³⁰ is bicyclic heterocyclylalkyl substituted with R^d, R^e, R^f, and R^f1.
The compound of any one of claims 1 to 3 and 8, or a pharmaceutically acceptable salt thereof, wherein the bicyclic heterocyclylalkyl of R³⁰ is hexahydro-1H-pyrrolizin-7a-ylalkyl where hexahydro-1H-pyrrolizin-7a-yl is substituted with R^d, R^e, R^f, and R^f1.
The compound of any one of claims 1 to 3, 8, and 9, or a pharmaceutically acceptable salt thereof, wherein the bicyclic heterocyclylalkyl of R³⁰ is hexahydro-1H-pyrrolizin-7a-ylmethyl, where hexahydro-1H-pyrrolizin-7a-yl is substituted with R^d, R^e, R^f, and R^f1.
The compound of any one of claims 1 to 3, and 8 to 10, or a pharmaceutically acceptable salt thereof, wherein the bicyclic heterocyclylalkyl of R³⁰ is a ring of formula:

and is substituted with R^e, R^f, and R^f1.
The compound of any one of claims 1 to 3, 8 to 10, or a pharmaceutically acceptable salt thereof, wherein R^f1 is hydrogen and the bicyclic heterocyclylalkyl of R³⁰ is a ring of formula:
The compound of any one of claims 1 to 3, 8 to 10, and 12, or a pharmaceutically acceptable salt thereof, wherein R^f1 is hydrogen and the bicyclic heterocyclylalkyl of R³⁰ is a ring of formula:
The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R^d and R^g are independently haloalkenyl, alkylidenyl, deuterioalkylidenyl, haloalkylidenyl, or alkoxyalkylidenyl.
The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R^d and R^g are alkylidenyl.
The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R^d and R^g are methylidenyl.
The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein Q¹ is alkylene.
The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein Q¹ is methylene, ethylene, -CH (CH₃) -, or -C (CH₃) ₂-.
The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein Q¹ is methylene.
The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl wherein (a) heterocyclyl is substituted with Rⁿ, R^o, R^p, and R^q and (b) bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiroheterocyclyl are independently substituted with R^r, R^s, and R^t.
The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form heterocyclyl substituted with Rⁿ, R^o, R^p, and R^q.
The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, wherein each ring independently is substituted with R^r, R^s, and R^t.
The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, or homomorpholin-1-yl, each ring substituted with Rⁿ, R^o, R^p, and R^q.
The compound of any one of claims 1 to 21 and 23, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, or homomorpholin-1-yl, each ring substituted with Rⁿ, R^o, R^p, and R^q where Rⁿ and R^o are independently selected from hydrogen, deuterium, methyl, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyano, or methoxy, R^p is hydrogen, deuterium, methoxymethyl, or fluoro, and R^q is hydrogen, deuterium, or fluoro.
The compound of any one of claims 1 to 21, 23, and 24, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form 3-methoxymethylazetidin-yl, 2-methoxymethyl-piperidin-1-yl, 3, 3, 4, 4-tetrafluoropyrrolidin-1-yl, morpholin-4-yl, 2, 6-dimethylmorpholin-4-yl, 2, 2-dimethylmorpholin-4-yl, 2- (trifluoromethyl) morpholin-4-yl, 2, 2-difluoromorpholin-4-yl, 2-methylmorpholin-4-yl, 3-methylmorpholin-4-yl, or 2- (difluoromethyl) morpholin-4-yl.
The compound of any one of claims 1 to 21 and 23 to 25, or a pharmaceutically acceptable salt thereof, wherein R³⁹ and R⁴⁰ together with the nitrogen atom to which they are attached form morpholin-4-yl, 2, 6-dimethylmorpholin-4-yl, 2, 2-dimethylmorpholin-4-yl, 2- (trifluoromethyl) morpholin-4-yl, 2, 2-difluoromorpholin-4-yl, 2-methylmorpholin-4-yl, 3-methylmorpholin-4-yl, or 2- (difluoromethyl) morpholin-4-yl.
The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein R^c, R^f, and Rⁱ are independently hydrogen, deuterium, methyl, ethyl, methoxy, ethoxy, methyloxy, ethyloxy, chloro, or fluoro.
The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R^c, R^f, and Rⁱ are each hydrogen.
The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R^c, R^f, and Rⁱ are independently methyl, methoxy, methyloxy, chloro, or fluoro.
The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein R^c1, R^f1, and Rⁱ¹ are independently selected from hydrogen, deuterium, and fluoro.
The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein R^c1, R^f1, and Rⁱ¹ are each hydrogen.
The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein Z is O.
The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R¹ is:
The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein R⁵ is -Q-R³⁷ where Q is a bond and R³⁷ is phenyl or naphthyl substituted with R^aa, R^bb, R^cc and R^dd.
The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R⁵ is -Q-R³⁷ where Q is a bond and R³⁷ is phenyl or naphthyl substituted with R^aa, R^bb, R^cc and R^dd where R^aa and R^bb are independently selected from hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cycloalkyl, amino, cyano, and hydroxyalkyl, R^cc is hydrogen, fluoro, or alkynyl, and R^dd is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl.
The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R^aa and R^bb independently selected from hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, difluoromethyl, trifluoromethoxy, hydroxy, methyl, ethoxy, cyclopropyl, amino, cyano, and hydroxymethyl, R^cc is hydrogen, ethynyl, 2-cyanovinyl, 2-cyanoethyn-1-yl, or fluoro, and R^dd is hydrogen, methyl, fluoro, amino, or cyclopropyl.
The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R⁵ is -Q-R³⁷ where Q is a bond and R³⁷ is:
The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R⁵ is -Q-R³⁷ where Q is a bond and R³⁷ is:
The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein R⁵ is -Q-R³⁷ where Q is a bond and R³⁷ is:

.
The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein R² is hydrogen, halo, or alkyl, and R³ is hydrogen, halo, cycloalkyloxy, or alkyl.
The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein R² and R³ are each hydrogen.
The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein R² is hydrogen or chloro and R³ is hydrogen, fluoro, or cyclopropyloxy.
The compound of any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein R² is hydrogen and R³ is fluoro.
A pharmaceutical composition comprising a compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
A method of treating cancer in a patient comprising administering to the patient, a therapeutically effective amount of a compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition of claim 44.
The method of claim 45, wherein the cancer is non-small cell lung cancer, colorectal cancer, or pancreatic cancer.
The method of claim 45 or 46, wherein the compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition of claim 44 is administered in combination with at least one additional anticancer agent.