BIFUNCTIONAL COMPOUNDS FOR DEGRADING KRAS G12D VIA UBIQUITIN PROTE ASOME PATHWAY

Related Applications

This application claims priority to, and the benefit of, International Application No. PCT/CN2022/117697, filed on September 8, 2022, and International Application No. PCT/CN2023/072897, filed on January 18, 2023, the contents of each of which are incorporated herein by reference in their entireties.

Field of the disclosure

The present disclosure provides certain bifunctional compounds that cause degradation of K-ras G12D via ubiquitin proteasome pathway and are therefore useful for the treatment of diseases mediated by K-ras G12D. 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 pl20GAP 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.l995;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-KB 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. Besides AMG5 10, which is an approved drug for treating K-Ras G12C driven cancers, several other K- Ras G12C covelent inhibitors, including 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). Compared to K-ras G12C mutant, since K- Ras G12D mutant, does not contain non-native cysteine residue and cycle through inactive state at extremely low rate, thus making K-Ras G12D mutant specific drug discovery more challenging. As an alternative to inhibition, removal of K-Ras G12D protein would eliminate K-Ras G12D activity as well as any protein interaction or scaffolding function of K-Ras G12D. Accordingly, there is a need for bifunctional molecules that could recruit K-Ras G12D to a ubiquitin ligase and thereby causing ubiquitylation and proteasomal degradation of K-Ras G12D. The present disclosure fulfills this and related needs.

Summary

In a first aspect, provided is a compound of Formula (IA): 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; m is 1 or 2, and n is 1, 2, or 3;

R ¹ is hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, hydroxy, hydroxylalkyl, alkoxy alkyl, cyano, or cyanomethyl, provided R ¹ is not attached to the ring -NH-;

R ^1a is hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, hydroxy, hydroxylalkyl, or alkoxyalkyl, provided R ^1a is not attached to the ring -NH-; or when R ¹ and R ^1a are attached to the carbon atoms of the ring that are opposite or diagonal to each other, then R ¹ and R ^1a can combine to form -(CH2) _Z - where (z is 1, 2, or 3), or -CH=CH -;

R ^1b is a bond to L, hydrogen, deuterium, alkyl, alkylidenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, cyanomethyl, cyanoethyl, or 2-cyanovinyl, provided R ^1b is not attached to the ring -NH-;

R ^1c is hydrogen or alkyl, provided R ^1c is not attached to the ring -NH-;

R ² is hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, or cyano, provided that R ² is absent when two of U, V, and W are N;

R ³ is a bond to L, hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, cycloalkyl, cycloalkyloxy, hydroxy, or cyano; R ⁴ is -Z-R ⁶ where Z is a bond, O, NH, N(alkyl), or S; and R ⁶ is heterocyclylalkyl, fused heterocyclylalkyl, bicyclic heterocyclyl, bicyclic heterocyclylalkyl, fused bicyclic heterocyclyl, fused bicyclic heterocyclylalkyl, tricyclic heterocyclyl, or tricyclic heterocyclylalkyl, wherein:

(1) fused heterocyclyl of fused heterocyclylalkyl is substituted with R ^a , R ^b , and R ^c where R ^a is =CR ⁷ R ⁸ ;

(2) heterocyclyl of heterocyclylalkyl and bicyclic heterocyclyl, by itself or as part of bicyclic heterocyclylalkyl, are substituted with R ^d , R ^c , and R ^f where R ^d is =CR ⁹ R ¹⁰ ; and

(3) fused bicyclic heterocyclyl, by itself or as part of fused bicyclic heterocyclylalkyl, and tricyclic heterocyclyl, by itself or as part of tricyclic heterocyclylalkyl are independently substituted with R ^g , R ^h , and R ¹ where R ^g is =CR ⁿ R ¹² ; where:

R ⁷ , R ⁹ , and R ¹¹ are independently a bond to L, hydrogen, deuterium, alkyl, fluoro, or haloalkyl;

R ⁸ , R ¹⁰ , and R ¹² are independently hydrogen, deuterium, alkyl, halo, haloalkyl, cyano, alkyloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, phenyl, or heteroaryl; or independently of each other, R ⁷ and R ⁸ , R ⁹ and R ¹⁰ , and R ¹¹ and R ¹² together with the carbon atom to which they are attached form cycloalkylene optionally substituted with alkyl, halo, alkoxy, or hydroxy;

R ^b , R ^c , and R ^b are independently a bond to L, hydrogen, alkyl, halo, alkoxy, alkoxyalkyl, hydroxy, or -(alkylene) _n i-OC(O)NR ¹³ R ^13a , wherein nl is 0 or 1, R ¹³ is hydrogen, deuterium, alkyl, deuterioalkyl, haloalkyl, haloalkoxyalkyl, or alkoxyalkyl, and R ^13a is hydrogen, alkyl, deuterioalkyl, cycloalkyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, or heterocyclyl substituted with Ri and R ^k independently selected from alkyl, halo, and haloalkyl; or R ¹³ and R ^13a together with the nitrogen atom to which they are attached form heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiro heterocyclyl wherein (a) heterocyclyl is substituted with R ^m , R ⁿ , R°, and R ^p where R ^m and R ⁿ are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, haloalkoxy, cyano, alkoxy and hydroxy, R° is hydrogen, deuterium, alkylidene, deuterioalkylidene, alkenyl, alkynyl, fluoro, alkoxyalkyl, alkylcarbonyl, haloalkylcarbonyl, or alkylsulfonyl, and R ^p is hydrogen, deuterium, or fluoro and (b) bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiro heterocyclyl are independently substituted with R ^q , R ^r , and R ^s independently selected from hydrogen, deuterium, alkyl, alkylthio, halo, haloalkyl, haloalkoxy, cyano, alkoxy, and hydroxy;

R ^c , R ^f , and R ¹ are independently a bond to L, hydrogen, alkyl, halo, alkoxy, alkoxyalkyl, or hydroxy, provided that one of R ^1b , R ³ , R ⁷ , R ⁹ , R ¹¹ , R ^b , R ^c , R ^b , R ^c , R ^f , and R ¹ is a bond to L;

R ⁵ is -Q-R ¹⁴ where Q is bond, alkylene, or -C(=O)-; and R ¹⁴ is cycloalkyl, fused cycloalkyl, fused spiro cycloalkyl, aryl, aralkyl, heteroaryl, fused heteroaryl, or heteroaralkyl wherein aryl, aryl in aralkyl, heteroaryl, fused heteroaryl, and heteroaryl in heteroaralkyl are independently substituted with R ^l , R ^u , R ^v , and R ^w wherein R ^l and R ^u are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R ^v is hydrogen, alkenyl, alkynyl, cyanoalkenyl, cyanoalkynyl, or halo, and R ^w 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;

Degron is an E3 ligase ligand selected from:

(a) a group of formula (i);

(b) a group of formula (ii);

(d) a group of formula (iv): (f) a group of formula (vi):

(vi)

(g) a group of formula (vii):

(h) a group of formula (viii): where:

R ¹⁵ and R ¹⁶ are hydrogen, alkyl, cycloalkyl, or alkylcarbonyloxy;

Y ^a is CH or N; Z ^a is a bond, -CH2-, -NH-, O, or -NHC(O)- where NH of -NHC(O)- is attached to Y ^a ; ring A is a ring of formula (a), (b), or (c): where:

X ¹ , X ² , X ³ ’ and X ⁴ are independently a bond, -alkylene-, alkynylene, -O-, - (O-alkylene)-, -(alkylene-O)-, -(NR ^gg -alkylene)-, -(alkylene-NR ^hh )-, -NH-, -N(alkyl)-, -C(=O)-, -(alkylene)-heterocyclylene-, cycloalkylene, -NR ^jj C(=O)-, or -C(=O)NR ^kk -, where R ^gg , R ^hh , R ^jj , and R ^kk are independently hydrogen, alkyl, or cycloalkyl and each alkylene is optionally substituted with one or two fluoro; R ^aa , R ^bb , R ^cc , and R ^dd are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano;

R ²⁰ and R ²¹ are independently hydrogen or alkyl; or R ²⁰ and R ²¹ together with the carbon to which they are attached form >C=O; and

R ²² is hydrogen or alkyl; ring B is phenylene, cyclylaminylene, a 5- or 6-membered monocyclic heteroarylene, or a 9- or 10-membered fused bicyclic heteroarylene, wherein each heteroarylene ring contains one to three nitrogen ring atoms and further wherein the phenylene, cyclylaminylene, and heteroarylene are independently substituted with R ^cc and R ^ff independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; and

R ¹⁷ , R ¹⁸ , and R ¹⁹ are alkyl, hydroxyalkyl, cycloalkyl or heterocyclyl wherein cycloalkyl and heterocyclyl are substituted with R ¹ ™ ¹¹ selected from hydrogen, alkyl, halo, haloalkyl, alkoxyl, haloalkoxyl, cyano, alkylcarbonyl, alkylcarbonylamino, or -COR ²³ where R ²³ is alkyl, hydroxalkyl, cycloalkyl or heterocyclyl, wherein cycloalkyl and heterocyclyl are substituted with R ⁿⁿ selected from hydrogen, alkyl, halo, haloalkyl, alkoxyl, haloalkoxyl, cyano, alkylcarbonyl, and alkylcarbonylamino; and

W ^a is bond, O, S, or alkylene; and

L is -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ - where:

Z ¹ is a bond, alkylene, -NR”-, -O-, -(alkylene-O)-, -C(O)-, -S(O)2-, -NR’(CO)-, or -C(O)NR-;

Z ² is a bond, -alkylene, -NR”-, -O-, -C(O)-, -S(O) ₂ -, -NR’(CO)-, -C(O)NR-, phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with R ^ww and R ^xx independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy;

Z ³ is a bond, alkylene, alkynylene, -(alkylene -NR”)-, -(NR”-alkylene)-, -O-, -C(O)- , -NR”-, -(O-alkylene)d-, -(alkylene-O)d-, cycloalkylene, spiro cyclolalkylene, phenylene, heteroarylene, heterocyclylene, fused heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R ^uu and R ^vv independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, amino, alkylamino, and dialkylamino;

Z ⁴ is a bond, alkylene, alkynylene, -C(O)NR-, -NR’(CO)-, -O-, -NR”-, -(O- alkylene) _c -, -(alkylene-O)c-, cycloalkylene, spiro cyclolalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, spiro heterocyclylene, or 11 to 13 membered spiro heterocyclylene, where each ring is substituted with R ^ss and R ^tt independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy;

Z ⁵ is a bond, alkylene, alkynylene, -SO2-, -SO2NR-, -NR’SO2-, -C(O)-, - C(O)N(R)-, -NR’(CO)-, -(O-alkylene)b-, -(alkylene-O)b-, -©(CH2)7-, -O(CH2)8-, cycloalkylene, or heterocyclylene, where each ring is substituted with R ^qq and R" independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy;

Z ⁶ is a bond, alkylene, -C(O)NR-, -NR’(CO)-, -S(O) ₂ NR-, -NR’S(O) ₂ -, -(O- alkylene) _a -, -(alkylene-O)a-, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, spiro heterocyclylene, -O-heterocyclylene-, -heterocyclylene-C(O)-, where each ring is substituted with R ⁰⁰ and R ^pp independently selected from hydrogen, deuterium, alkyl, alkoxy, cyano, hydroxy, carboxy, halo, haloalkyl, and haloalkoxy; and where each alkylene of -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ - is independently one to eight carbon atoms, R, R’ and R” is independently hydrogen or alkyl, each a, b, c, and d is independently an integer selected from 1 to 6, and each alkylene of -Z ¹ -, -Z ² -, -Z ³ -, -Z ⁴ -, -Z ⁵ - and

-Z ⁶ - is substituted with R ^yy and R ^zz where R ^yy is hydrogen or deuterium and R ^zz is hydrogen, deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocyclyl, aryl, or monocyclic heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and monocyclic heteroaryl are substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; provided that at least one of -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ - is not a bond; wherein when several adjacent groups of Z ¹ to Z ⁶ are a bond, the adjacent groups represent one bond; or a pharmaceutically acceptable salt thereof.

In a second 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; m is 1 or 2, and n is 1, 2, or 3;

R ¹ is hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, hydroxy, hydroxylalkyl, alkoxy alkyl, cyano, or cyanomethyl, provided R ¹ is not attached to the ring -NH-;

R ^1a is hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, hydroxy, hydroxylalkyl, or alkoxyalkyl, provided R ^1a is not attached to the ring -NH-; or when R ¹ and R ^1a are attached to the carbon atoms of the ring that are opposite or diagonal to each other, then R ¹ and R ^1a can combine to form -(CH2) _Z - where (z is 1, 2, or 3), or -C I I C I I -;

R ^1b is a bond to L, hydrogen, deuterium, alkyl, alkylidenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, cyanomethyl, cyanoethyl, or 2-cyanovinyl, provided R ^1b is not attached to the ring -NH-;

R ^1c is hydrogen or alkyl, provided R ^lc is not attached to the ring -NH-;

R ² is hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, or cyano, provided that R ² is absent when two of U, V, and W are N;

R ³ is a bond to L, hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, cycloalkyl, cycloalkyloxy, hydroxy, or cyano;

R ⁴ is -Z-R ⁶ where Z is a bond, O, NH, N(alkyl), or S; and R ⁶ is heterocyclylalkyl, fused heterocyclylalkyl, bicyclic heterocyclyl, bicyclic heterocyclylalkyl, fused bicyclic heterocyclyl, fused bicyclic heterocyclylalkyl, tricyclic heterocyclyl, or tricyclic heterocyclylalkyl, wherein:

(1) fused heterocyclyl of fused heterocyclylalkyl is substituted with R ^a , R ^b , and R ^c where R ^a is =CR ⁷ R ⁸ ;

(2) heterocyclyl of heterocyclylalkyl and bicyclic heterocyclyl, by itself or as part of bicyclic heterocyclylalkyl, are substituted with R ^d , R ^c , and R ^f where R ^d is R ^d is =CR ⁹ R ¹⁰ ; and (3) fused bicyclic heterocyclyl, by itself or as part of fused bicyclic heterocyclylalkyl, and tricyclic heterocyclyl, by itself or as part of tricyclic heterocyclylalkyl are independently substituted with R ^g , R ^h , and R ¹ where R ^g is =CR ⁿ R ¹² ; where:

R ⁷ , R ⁹ , and R ¹¹ are independently a bond to L, hydrogen, deuterium, alkyl, fluoro, or haloalkyl;

R ⁸ , R ¹⁰ , and R ¹² are independently hydrogen, deuterium, alkyl, halo, haloalkyl, cyano, alkyloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, phenyl, or heteroaryl; or independently of each other, R ⁷ and R ⁸ , R ⁹ and R ¹⁰ , and R ¹¹ and R ¹² together with the carbon atom to which they are attached form cycloalkylene optionally substituted with alkyl, halo, alkoxy, or hydroxy;

R ^b , R ^c , and R ^h are independently a bond to L, hydrogen, alkyl, halo, alkoxy, alkoxyalkyl, hydroxy, or -(alkylene)ni-OC(O)NR ¹³ R ^13a (wherein nl is 0 or 1, R ¹³ is hydrogen, deuterium, alkyl, deuterioalkyl, haloalkyl, haloalkoxyalkyl, or alkoxyalkyl, and R ^13a is hydrogen, alkyl, deuterioalkyl, cycloalkyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, or heterocyclyl substituted with Ri and R ^k independently selected from alkyl, halo, and haloalkyl; or R ¹³ and R ^13a together with the nitrogen atom to which they are attached form heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, or spiro heterocyclyl wherein (a) heterocyclyl is substituted with R ^m , R ⁿ , R°, and R ^p where R ^m and R ⁿ are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, haloalkoxy, cyano, alkoxy and hydroxy, R° is hydrogen, deuterium, alkylidene, deuterioalkylidene, alkenyl, alkynyl, fluoro, alkoxyalkyl, alkylcarbonyl, haloalkylcarbonyl, or alkylsulfonyl, and R ^p is hydrogen, deuterium, or fluoro and (b) bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiro heterocyclyl are independently substituted with R ^q , R ^r , and R ^s independently selected from hydrogen, deuterium, alkyl, alkylthio, halo, haloalkyl, haloalkoxy, cyano, alkoxy, and hydroxy;

R ^c , R ^f , and R ¹ are independently a bond to L, hydrogen, alkyl, halo, alkoxy, alkoxyalkyl, or hydroxy, provided that one of R ^1b , R ³ , R ⁷ , R ⁹ , R ¹¹ , R ^b , R ^c , R ^b , R ^c , R ^f , and R ¹ is a bond to L;

R ⁵ is -Q-R ¹⁴ where Q is bond, alkylene, or -C(=O)-; and R ¹⁴ is cycloalkyl, fused cycloalkyl, fused spiro cycloalkyl, aryl, aralkyl, heteroaryl, fused heteroaryl, or heteroaralkyl wherein aryl, aryl in aralkyl, heteroaryl, fused heteroaryl, and heteroaryl in heteroaralkyl are independently substituted with R ^l , R ^u , R ^v , and R ^w wherein R ^l and R ^u are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R ^v is hydrogen, alkenyl, alkynyl, cyanoalkenyl, cyanoalkynyl, or halo, and R ^w 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;

Degron is an E3 ligase ligand selected from:

(a) a group of formula (i);

(b) (c) a group of formula (iii):

(d) a group of formula (iv):

(e) a group of formula (v):

(f) a group of formula (vi):

where:

R ¹⁵ and R ¹⁶ are hydrogen, alkyl, cycloalkyl, or alkylcarbonyloxy;

Y ^a is CH or N;

Z ^a is a bond, -CH2-, -NH-, O, or -NHC(O)- where NH of -NHC(O)- is attached to Y ^a ; ring A is a ring of formula (a), (b), or (c): where:

X ¹ , X ² , X ³ ’ and X ⁴ are independently a bond, -alkylene-, -O-, -(O-alkylene)-

-(alkylene-O)-, -(NR ^gg -alkylene)-, -(alkylene -NR ^hh )-, -NH-, -N(alkyl)-, -C(=O)-,

-NR ^jj C(=O)-, or -C(=O)NR ^kk -, where R ^gg , R ^hh , R ^jj , and R ^kk are independently hydrogen, alkyl, or cycloalkyl and each alkylene is optionally substituted with one or two fluoro; R ^aa , R ^bb , R ^cc , and R ^dd are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano;

R ²⁰ and R ²¹ are independently hydrogen or alkyl; or R ²⁰ and R ²¹ together with the carbon to which they are attached form >C=O; and

R ²² is hydrogen or alkyl; ring B is phenylene, cyclylaminylene, a 5- or 6-membered monocyclic heteroarylene, or a 9- or 10-membered fused bicyclic heteroarylene, wherein each heteroarylene ring contains one to three nitrogen ring atoms and further wherein the phenylene, cyclylaminylene, and heteroarylene are independently substituted with R ^cc and R ^ff independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; and R ¹⁷ , R ¹⁸ , and R ¹⁹ are alkyl, hydroxyalkyl, cycloalkyl or heterocyclyl wherein cycloalkyl and heterocyclyl are substituted with R ^mm selected from hydrogen, alkyl, halo, haloalkyl, alkoxyl, haloalkoxyl, cyano, alkylcarbonyl, alkylcarbonylamino, or -COR ²³ where R ²³ is alkyl, hydroxalkyl, cycloalkyl or heterocyclyl, wherein cycloalkyl and heterocyclyl are substituted with R ⁿⁿ selected from hydrogen, alkyl, halo, haloalkyl, alkoxyl, haloalkoxyl, cyano, alkylcarbonyl, and alkylcarbonylamino; and

W ^a is bond, O, S, or alkylene; and

L is -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ - where:

Z ¹ is a bond, alkylene, -NR”-, -O-, -(alkylene-O)-, -C(O)-, -S(O)2-, -NR’(CO)-, or -C(O)NR-;

Z ² is a bond, -alkylene, -NR”-, -O-, -C(O)-, -S(O) ₂ -, -NR’(CO)-, -C(O)NR-, phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with R ^ww and R ^xx independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy;

Z ³ is a bond, alkylene, alkynylene, -(alkylene -NR”)-, -(NR”- alkylene)-, -O-, - C(O)-, -NR”-, -(O-alkylene)d-, -(alkylene-O)d-, cycloalkylene, spiro cyclolalkylene, phenylene, heteroarylene, heterocyclylene, fused heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R ^uu and R ^vv independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino;

Z ⁴ is a bond, alkylene, alkynylene, -C(O)NR-, -NR’(CO)-, -O-, -NR”-, -(O- alkylene) _c -, -(alkylene-O)c-, cycloalkylene, spiro cyclolalkylene, phenylene, monocyclic heteroarylene, heterocyclylene, bicyclic heterocyclylene, bridged heterocyclylene, fused heterocyclylene, spiro heterocyclylene, or 11 to 13 membered spiro heterocyclylene, where each ring is substituted with R ^ss and R ^tt independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy;

Z ⁵ is a bond, alkylene, alkynylene, -C(O)-, -C(O)N(R)-, -NR’(CO)-, -(O- alkylene)b-, -(alkylene-O)b-, -O(CH ₂ )7-, -O(CH2)8-, cycloalkylene, or heterocyclylene, where each ring is substituted with R ^qq and R ^rr independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy; Z ⁶ is a bond, alkylene, -C(O)NR-, -NR’(CO)-, -S(O) ₂ NR-, -NR’S(O) ₂ -, -(O- alkylene) _a -, -(alkylene-O)a-, phenylene, monocyclic heteroarylene, or heterocyclylene, where each ring is substituted with R ⁰⁰ and R ^pp independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy; and where each alkylene of -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ - is independently one to eight carbon atoms, R, R’ and R” is independently hydrogen or alkyl, each a, b, c, and d is independently an integer selected from 1 to 6, and each alkylene of -Z ¹ -, -Z ² -, -Z ³ -, -Z ⁴ -, -Z ⁵ - and

-Z ⁶ - is substituted with R ^yy and R ^zz where R ^yy is hydrogen or deuterium and R ^zz is hydrogen, deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocyclyl, aryl, or monocyclic heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and monocyclic heteroaryl are substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano; provided that at least one of -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ - is not a bond; wherein when several adjacent groups of Z ¹ to Z ⁶ are a bond, the adjacent groups represent one bond; or a pharmaceutically acceptable salt thereof.

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

In a fourth 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 (IA) or (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 fifth aspect, provided is a method of inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with a compound of Formula (IA) or (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 sixth 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 (IA) or (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 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 (IA) or (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 an eighth aspect, provided is a compound of Formula (IA) or (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 a ninth aspect, provided is a compound of Formula (IA) or (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 tenth aspect, provided is a compound of Formula (IA) or (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 an eleventh aspect, provided is a compound of Formula (IA) or (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 a twelfth eleventh aspect, provided is a compound of Formula (IA) or (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 (IA) or (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

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 or branched saturated monovalent hydrocarbon radical of one to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl, pentyl, and the like.

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

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

“Alkynylene” means a linear or branched unsaturated divalent hydrocarbon radical of two to six carbon atoms containing a triple bond, e.g., 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 (CH ₃ CH =), hexylidenyl (CH ₃ (CH ₃ ) ₄ CH=), 2-propylidenyl (=C(CH ₃ )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.

“Alkylsulfonyl” means a -SO ₂ R ^z radical where R ^z is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like.

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

“Alkylcarbonyloxy” means an -OC(O)R ^z group, where R ^z is alkyl, as defined herein.

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

“Alkylcarbonylamino” means a -NR ^Z ’C(O)R ^Z radical where R ^z is alkyl and R ^z ’ is H or alkyl, as defined above, e.g., methylcarbonylamino, ethylcarbonylamino, and the like.

“Alkylcarbonyl” means a -C(O)R ^Z radical where R ^z is alkyl as defined herein, e.g., methylcarbonyl, ethylcarbonyl, and the like.

“Alkylcarbonyloxy” means a -OC(O) R ^z radical where R ^z is alkyl as defined above, e.g., methylcarbonyloxy, ethylcarbonyloxy, and the like.

“Amino” means a -NH2.

“Alkylamino” means -NHR ^Z radical where R ^z is alkyl is as defined above e.g., methylamino, ethylamino, propylamino, and the like.

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

“Arylene” means a divalent aryl (as defined above) radical e.g., phenylene or naphthylene.

“Aralkyl” means a -(alkylene)-R ^z radical where R ^z 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- IH-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- IH-pyrrolizinylethyl, and the like.

“Bicyclic heterocyclylene” means a saturated or unsaturated divalent fused bicyclic group of 9 to 12 ring atoms in which one, two, or three ring atoms are heteroatom independently selected from N, O, and S(O) _n , where n is an integer selected from 0 to 2 inclusive, the remaining ring atoms being carbon, unless stated otherwise. Additionally, one or two ring carbon atoms of the bicyclic heterocyclylene ring can optionally be replaced by a -CO- group. More specifically the term bicyclic heterocyclylene includes, but is not limited to, hexahydrofuro[3,2-b]furan-3,6-diyl, and the like. When the heterocyclylene ring is unsaturated it can contain one or two ring double bonds provided that the ring is not aromatic.

“Bridged heterocyclyl” means a saturated monovalent bicyclic ring having 5 to 8 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CR ^z R ^z’ ) _n group where n is an integer selected from 1 to 3 inclusive and R ^z and R ^z ’ are independently H or methyl (also may be referred to herein as “bridging” group) and further wherein one or two ring carbon atoms, including an atom in the bridging group, is replaced by a heteroatom selected from N, O, and S(O) _n , where n is an integer selected from 0 to 2 inclusive. Examples include, but are not limited to, 3,8-diazabicyclo[3.2. l]octa-3-yl, and the like.

“Bridged heterocyclylene” means a saturated divalent bicyclic ring having 5 to 8 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CR ^z R ^z’ ) _n group where n is an integer selected from 1 to 3 inclusive and R ^z and R ^z’ are independently H or methyl (also may be referred to herein as “bridging” group) and further wherein one or two ring carbon atoms, including an atom in the bridging group, is replaced by a heteroatom selected from N, O, and S(O) _n , where n is an integer selected from 0 to 2 inclusive. Bridged heterocyclylene is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano unless stated otherwise. Examples include, but are not limited to, 3,8- diazabicyclo[3.2.1]octa-3,8-diyl, 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.

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

“Cycloalkylene” means a divalent saturated hydrocarbon radical of three to six carbon atoms, otherwise e.g., 1,1 -cyclopropylene, 1,1 -cyclobutylene, 1 ,4-cyclohexylene, 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.

“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), -CH ₂ C=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), -CH ₂ C≡C(CN), and the like.

“Carboxy” means -COOH.

“Cyclylaminylene” means a saturated divalent monocyclic ring of 4 to 8 ring atoms in which one ring atom is nitrogen, the remaining ring atoms being C. More specifically, the term cyclylaminyl includes, but is not limited to, pyrrolidinylene, piperidinylene, homopiperidinylene, and the like.

“Deuterium” mean refers to ² H or D.

“Deuterioalkyl” mean alkyl as defined above, which is substituted with one, two, or three deuterium.

“Alkylidenyl” means refers to a group of formula R= where R is deuterioalkyl as defined above. Examples include, but are not limited to, methylidenyl (D2C=), ethylidenyl (CH ₃ ,CD=), hexylidenyl (CH ₃ (CH ₂ ) ₄ CD=) , and the like.

“Deuterohaloalkyl” mean haloalkyl as defined herein, which is substituted with one, two, or three deuterium.

“Dialkylamino” means -NR ^z’ R ^z’ radical where R ^z’ and R ^z" is alkyl as defined above e.g., dimethylamino, diethylamino, methylpropylamino, 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-lH-pyrrolo[2,l-a]isoindol-9b(5H)-yl, 2,3-dihydro- lH-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- IH-pyrrolizinylethyl, 2,3-dihydro-lH-pyrrolo[2, l-a]isoindol- 9b(5H)-ylmethyl, 2,3-dihydro-lH-pyrrolo[l,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-l,3,5-triene, bicyclo[4.2.0]octa-l,3,5-triene, and the like.

“Fused spiro cycloalkyl” 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” as used herein, 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 and the remaining ring atoms being carbon, and further wherein two adjacent ring atoms of the monocyclic ring is fused to two adjacent ring members of a phenyl or a five or six membered heteroaryl, each as defined herein, unless stated otherwise. The nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized 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][l,4]-dioxinyl, 2-oxabicyclo[3.1.0]hexanyl, indolin-2-one- 1 -yl, indolinyl, and the like.

“Fused heterocyclylene” as used herein, refers to a divalent bicyclic ring in which two adjacent ring atoms of a saturated monocyclic ring of 4 to 7 ring atoms having one or two heteroatoms independently selected from N, O, and S(O)n (where n is 0, 1, or 2) and the remaining ring atoms being carbon, are fused to two adjacent ring members of a phenyl or a five or six membered heteroaryl, each as defined herein, unless stated otherwise. The nitrogen atom is optionally oxidized or quatemized 1. The fused heterocyclylene can be attached at any two atoms of the ring. Representative examples include, but are not limited to, 1,2,3,4-tetrahydroquinolin- 1,4-diyl, 3,4-dihydro-2H-benzo[b][l,4]oxazin-5,8-diyl, 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., -CH2CI, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH ₃ )2, and the like. When the alkyl is substituted with only fluorine atom(s), it can be referred to in this Application as fluoroalkyl.

“Haloalkoxy” means a -OR ^Z radical where R ^z is haloalkyl as defined above e.g., -OCF3, -OCHF2, and the like. When R ^z is haloalkyl where the alkyl is substituted with only fluorine atom(s), it is referred to in this Application as fluoroalkoxy.

“Haloalkoxyalkyl” means a -(alkylene)OR ^z radical where R ^z is haloalkyl as defined above, e.g., trifluoromethoxyalkyl, and the like.

“Halocarbonyl” means a -C(O)R ^Z radical where R ^z is haloalkyl, as defined herein, e.g., trifluoromethylcarbonyl, difluoromethylcarbonyl, 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 present on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxy-ethyl, 2-hydroxypropyl, 3 -hydroxypropyl, l-(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 l-(hydroxymethyl)-2-hydroxyethyl.

“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 and is a monocyclic ring, it is also referred to herein as 5 -or 6-membered monocyclic heteroaryl or monocyclic heteroaryl. When the heteroaryl ring contains 9- or 10 ring atoms and is a fused bicyclic ring, it is also referred to herein as 9-or 10- membered 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.

“Heteroarylene” means a divalent heteroaryl radical as defined above, unless stated otherwise. Representative examples include, but are not limited to, benzimidazoldiyl e.g., benzimidazole-l,5-diyl, and the like. When the heteroarylene ring contains 5 or 6 ring atoms and is a monocyclic ring and is also referred to herein as monocyclic heteroarylene or as 5 -or 6-membered monocyclic heteroarylene e.g., pyrazolyl-1.4-diyl. When the heteroarylene ring contains 9 or 10 ring atoms and is a fused bicyclic ring, it is also referred to herein as 9-or 10-membered fused bicyclic heteroarylene.

“Heteroaralkyl” means a -(alkylene)-R ^z radical where R ^z 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 or monocyclic 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 selected from 0 to 2 inclusive, 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. 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 ^z radical where R ^z is heterocyclyl ring as defined above e.g., tetraydrofiiranylmethyl, piperazinylmethyl, morpholinylethyl, and the like.

“Heterocyclylene” means a saturated divalent monocyclic group of 4 to 6 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 selected from 0 to 2 inclusive, the remaining ring atoms being C, unless stated otherwise. Additionally, one or two ring carbon atoms in the heterocyclylene ring can optionally be replaced by a -CO- group. More specifically, the term heterocyclylene includes, but is not limited to, , piperidin- 1 ,4-diyl, azetidin- 1,3 -diyl, and the like. “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.

“Phenylene” refers to divalent phenyl.

The term “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, alkylthio, alkylsulfonyl, amino, alkylamino, dialkylamino, halo, haloalkyl, haloalkoxy, and cyano. In some embodiments, optionally substituted aryl is optionally substituted phenyl.

“Optionally substituted aralkyl” means -(alkylene)-R ^z where R ^z is optionally substituted aryl as defined above.

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

“Optionally substituted heteroaralkyl” means -(alkylene) -R ^z where R ^z is optionally substituted heteroaryl as defined above.

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

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

The phrase “optionally” or “optional” as used herein 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, the phrase “heteroaryl optionally substituted with alkyl” is intended to cover heteroaryl that is unsubstituted with alkyl and heteroaryl that is substituted with alkyl.

“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.

“Spiro cycloalkylene” means a saturated bicyclic divalent hydrocarbon ring having 6 to 12 ring atoms wherein the rings are connected through only one atom, the connecting atom is also called the spiroatom, most often a quaternary carbon (“spiro carbon”). Spiro cycloalkylene is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, and cyano, unless stated otherwise. Representative examples include, but are not limited to, spiro[3,5]nonandiyl e.g., spiro[3.5]nonane-2,7-diyl, and the like.

“Spiro heterocyclyl" means a saturated bicyclic monovalentvalent 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 inclusive, 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”).

“Spiro heterocyclylene" means a saturated bicyclic divalent 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 inclusive, 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”).

“Tricyclic heterocyclyl” means a saturated monovalent fused tricyclic ring of 9 to 14, preferably 12 to 14, ring atoms in which one, two, or three 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,

The present disclosure also includes protected derivatives of compounds of Formula (IA) or (I). For example, when compounds of Formula (IA) or (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 (IA) or (I) or a pharmaceutically acceptable salt thereof.

The term “prodrug” refers to a compound that is made more active in vivo. Certain compounds Formula (IA) or (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, /V-incthylgliicai inc, 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, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference in its entirety.

The compounds of Formula (IA) or (I) (and any embodiment thereof disclosed herein including specific compounds) may have asymmetric centers. Compounds of Formula (IA) or (I) (and any embodiment thereof disclosed herein including specific compounds) 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 (IA) or (I) (and any embodiment thereof disclosed herein including specific compounds) 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 (IA) or (I) (and any embodiment thereof disclosed herein including specific compounds) are within the scope of this disclosure.

The compounds of Formula (IA) or (I) (and any embodiment thereof disclosed herein including specific compounds) 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 disclosure, such as a compound of Formula (IA) or (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 ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³² P, ³³ P, ³⁵ S, ¹⁸ F, ³⁶ C1, ¹²³ I, and ¹²⁵ 1, respectively. Isotopically labeled compounds (e.g., those labeled with ³ H and ¹⁴ C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e., ³ H) and carbon-14 (i.e., ¹⁴ C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ² H) 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 (IA) or (I) (and any embodiment thereof disclosed herein including specific compounds) one or more hydrogen atoms are replaced by ² H or ³ H, or one or more carbon atoms are replaced by ¹³ C- or ¹⁴ C- enriched carbon. Positron emitting isotopes such as ¹⁵ O, ¹³ N, ¹¹ C, and ¹⁵ F 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.

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%, preferably ± 5%, wherein the recited value and the range (including the endpoints) are included.

The phrase alkylene optionally substituted with one or two fluoro in the definition of X ¹ , X ² , X ³ ’ and X ⁴ in Formula (IA) or (I) (and any embodiment thereof disclosed herein) (and similar phrases used to define other groups in Formula (IA) or (I)) is intended to cover alkylene that is unsubstituted and alkylene that is substituted one or two fluoro.

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 to which it is attached, where chemically feasible and valency rules permitting. For example, in the structure:

For example, in the structure of Formula (la):

R ² and R ³ groups are floating substituents and can replace the hydrogen atom of any one of U, V, and W of the portion of the quinazoline ring ring when U, V, and W are CH; and in the structure the R ^aa substituent of R ^aa , R ^bb and X ¹ , and similarly the R ^bb and X ¹ substituents, can replace hydrogen of any CH that is part of the benzo portion of the bicyclic ring that is not already substituted with R ^bb and X ¹ , and similarly R ^aa and X ¹ , and R ^aa and R ^bb substituents with respect to R ^bb and X ¹ , respectively.

Additionally, as used throughout the application, including in the embodiments, when a group is drawn out as divalent, the left bond of the divalent group is attached to the group which is to its left in the remainder of the molecule, and the right bond of the divalent group is attached to the group which is to its right in the remainder of the molecule. For example, in the following divalent groups the bond on the left of (a), (b) and (c) is attached to Z ⁶ of L in the following structure : and the on the right side of (a), (b), and (c) (i.e., X ¹ , X ² , and X ³ ) is attached to ring:

Similarly, for L i.e, -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ -, the left side in L (i.e., Z ¹ ) is attached to an atom of an R ⁴ group as denoted in this Application and Z ⁶ is attached to X ¹ , X ² , X ³ , or X ⁴ . For example, when L is a group of formula: and Degron is a group of formula (a), i.e., , the left bond of L (i.e., the -NH- group) is attached to X ² and the right hand bond of L (i.e., -SO2-) is attached to an R ⁴ group as denoted in this Application.

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 the disclosure made are disclosed in Compound Table 1 and 2 below:

Compound Table 1

Compound Table 2

Contemplated compounds of Formula IA are disclosed in table 3 and 4 below

Compound Table 3

Table 4.

5

Additional contemplated compounds of Formula (I) are disclosed below.

Embodiments:

In embodiments 1 to 300, the present disclosure includes:

1A. In embodiment 1A, the compound of Formula (IA) or a pharmaceutically acceptable salt thereof is a compound according to structure (IA’): where R ¹ , R ^1a , R ^1b , R ² , R ³ , R ⁴ , R ⁵ , n, m, L, U, V, W, and Degron are as defined in the first aspect of the Summary.

1. In embodiment 1, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is a compound according to structure (la): where R ¹ , R ^1a , R ^1b , R ² , R ³ , R ⁴ , R ⁵ , n, m, L, U, V, W, and Degron are as defined in the second aspect of the Summary. la. In embodiment la, the compound of embodiment IA or 1, a pharmaceutically acceptable salt is a compound according to structure (lb): where R ¹ , R ^1a , R ^1b , R ² , R ³ , R ⁴ , R ⁵ , n, m, L and Degron are as defined in the first or second aspect of the Summary, respectivley. lb. In embodiment lb, the compound of embodiment 1 A or 1, or a pharmaceutically acceptable salt is a compound according to structure (Ic): where R ¹ , R ^1a , R ^1b , R ² , R ³ , R ⁴ , R ⁵ , n, m, L and Degron are as defined in the first or second aspect of the Summary, respectively.

2. In embodiment 2, the compound of embodiment 1A, 1, la, or lb, or a pharmaceutically acceptable salt thereof, is wherein R ⁶ is fused heterocyclylalkyl where fused heterocyclyl of fused heterocyclylalkyl is substituted with R ^a , R ^b , and R ^c as defined therein.

3. In embodiment 3, the compound of embodiment 1 A, 1, la, or lb, or a pharmaceutically acceptable salt thereof, is wherein the fused heterocyclyl of fused heterocyclylalkyl of R ⁶ is isoindolinyl substituted with R ^a , R ^b , and R ^c as defined therein.

4. In embodiment 4, the compound of any one of embodiments 1 A to 3, or a pharmaceutically acceptable salt thereof, is wherein the fused heterocyclylalkyl of R ⁶ is a ring of formula: are as defined therein.

5. In embodiment 5, the compound of embodiment 1A, 1, la, or lb, or a pharmaceutically acceptable salt thereof, is wherein R ⁶ is heterocyclylalkyl, bicyclic heterocyclyl, or bicyclic heterocylalkylalkyl, where heterocyclyl of heterocyclylalkyl and bicyclic heterocyclyl, by itself or as part of bicyclic heterocyclylalkyl are substituted with R ^d , R ^e , and R ^f as defined therein.

6. In embodiment 6, the compound of embodiment 1A, 1, 1a, lb, or 5, or a pharmaceutically acceptable salt thereof, is wherein R ⁶ is heterocyclylalkyl where heterocyclyl of heterocyclylalkyl of R ⁶ is substituted with R ^d , R ^e , and R ^f as defined therein. 7. In embodiment 7, the compound of any one of embodiments 1A, 1, la, lb, 5 and 6, or a pharmaceutically acceptable salt thereof, is wherein the heterocyclylalkyl of R ⁶ is pyrrolidin-2- ylmethyl, piperidin-2-ylmethyl, or piperi din-3 -ylmethyl, preferably pyrrolidin-2-ylmethyl substituted with R ^d , R ^e , and R ^f as defined therein.

8. In embodiment 8, the compound of any one of embodiments 1A, 1, 1a, lb, and 5 to 7, or a pharmaceutically acceptable salt thereof, is wherein the heterocyclylalkyl of R ⁶ is pyrrolidin-2- ylmethyl of structure substituted with R ^e and R ^f , preferably R ⁶ is pyrrolidin-2-ylmethyl of structure hydrogen.

9. In embodiment 9, the compound of any one of embodiments 1A, 1, 1a, lb, and 5, or a pharmaceutically acceptable salt thereof, is wherein R ⁶ is bicyclic heterocyclalkylalkyl substituted with R ^d , R ^e , and R ^f as defined therein.

10. In embodiment 10, the compound of any one of embodiments 1A, 1, 1a, lb, 5, and 9, or a pharmaceutically acceptable salt thereof, is wherein the bicyclic heterocyclylalkyl of R ⁶ is hexahydro- 1 H-pyrrolizin-7 a-ylalkyl-d2, preferably, hexahydro- 1 H-pyrrolizin-7a-ylmethyl-d2, where hexahydro- lH-pyrrolizin-7a-yl is substituted with R ^d , R ^e , and R ^f as defined therein.

11. In embodiment 11, the compound of any one of embodiments 1A, 1, 1a, lb, 5, 9, and 10, or a pharmaceutically acceptable salt thereof, is wherein the bicyclic heterocyclylalkyl is a ring of formula: substituted with R ^e , and R ^f as defined therein. 12. In embodiment 12, the compound of any one of embodiments 1A, 1, la, lb, 5, and 9 to

11 , or a pharmaceutically acceptable salt thereof, is wherein the bicyclic heterocyclylalkyl of R ⁶ is a ring of formula: where R ^d , R ^e , R ^f , are as defined therein.

13. In embodiment 13, the compound of any one of embodiments 1A, 1, la, lb, 5, and 9 to 12, or a pharmaceutically acceptable salt thereof, is wherein the bicyclic heterocyclylalkyl of R ⁶ is a ring of formula:

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

14. In embodiment 14, the compound of embodiment 1A, 1, la, or lb, or a pharmaceutically acceptable salt thereof, is wherein R ⁶ 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 , and R ¹ as defined therein.

15 In embodiment 15, the compound of embodiment 1A, 1, la, lb, or 14, or a pharmaceutically acceptable salt thereof, is wherein R ⁶ is fused bicyclic heterocyclyl substituted with R ^g , R ^h , , and R ¹ as defined therein.

16. In embodiment 16, the compound of embodiment 1A, 1, la, lb, or 15, or a pharmaceutically acceptable salt thereof, is wherein the fused bicyclic heterocyclyl of R ⁶ is a ring of formula: where ring Al is phenyl or 5- or 6-membered heteroaryl and the fused bicyclic heterocyclyl is additionally substituted with R ^h and R ¹ where R ^g , R ^h and R ¹ are as defined as defined therein, preferably ring Al is phenyl or 5- or 6-membered heteroaryl substituted with R ^h and R ¹ as defined therein.

17. In embodiment 17, the compound of embodiment 1A, 1, la, lb, 15, or 16, or a pharmaceutically acceptable salt thereof, is wherein the fused bicyclic heterocyclyl of R ⁶ is a ring of formula: where ring Al is phenyl, pyrazolyl, pyridinyl, or pyrimidinyl, each ring substituted with R ^h and R ¹ as defined therein.

18. In embodiment 18, the compound of any one of embodiments 1A, 1, la, lb, and 14, or a pharmaceutically acceptable salt thereof, is wherein R ⁶ is fused bicyclic heterocylalkylalkyl where fused bicyclic heterocyclyl of fused bicyclic heterocyclylalkyl is substituted with R ^g , R ^h , and R ¹ as defined therein.

19. In embodiment 19, the compound of embodiment 1A, 1, la, lb, or 14, or a pharmaceutically acceptable salt thereof, is wherein fused bicyclic heterocyclyl of fused bicyclic heterocyclylalkyl of R ⁶ is a ring of formula: where ring Al is phenyl or 5- or 6-membered heteroaryl and the fused bicyclic heterocyclyl is additionally substituted with R ^h and R ¹ where R ^g , R ^h and R ¹ are as defined as defined therein.

20. In embodiment 20, the compound of embodiment 1A, 1, la, lb, 14, or 19, or a pharmaceutically acceptable salt thereof, is wherein the fused bicyclic heterocyclyl of fused bicyclic heterocyclylalkyl of R ⁶ is a ring of formula: where ring Al is phenyl, pyrazolyl, pyridinyl, or pyrimidinyl, each ring substituted with R ^b and R ¹ as defined therein.

21. In embodiment 21, the compound of any one of embodiments 1A, 1, la, lb, and 14 to 20, or a pharmaceutically acceptable salt thereof, is wherein the fused bicyclic heterocyclyl and fused bicyclic heterocyclyl of fused bicyclic heterocyclylalkyl of R ⁶ is 2,3 -dihydro- lH-pyrrolo[2,l- a]isoindol-9b(5H)-yl, 2,3-dihydro-lH-pyrrolo[l,2-a]indol-9a(9H)-yl, 1,3b, 4,5,6, 8-hexahydropyrrolo- [3,2-a]pyrrolizin-3b-yl, l-methyl-l,3b,4,5,6,8-hexahydropyrrolo[4,3-a]pyrrolizin-3b-y l, 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 l,2,3,5,10,10a-hexahydropyrrolo[l,2-b]isoquinolin-10a-yl, each ring substituted with R ^g , R ^h , and R ¹ as defined therein.

22. In embodiment 22, the compound of any one of embodiments 1A, 1, la, lb, and 14, or a pharmaceutically acceptable salt thereof, is wherein R ⁶ is tricyclic heterocyclyl substituted with R ^g , R ^b , and R ¹ as defined therein.

23. In embodiment 23, the compound of any one of embodiments 1A, 1, la, lb, and 14, or a pharmaceutically acceptable salt thereof, is wherein R ⁶ is tricyclic heterocyclylalkyl where tricyclic heterocyclyl of tricyclic heterocyclylalkyl is substituted with R ^g , R ^b , and R ¹ as defined therein.

24. In embodiment 24, the compound of any one of embodiments 1 A to 23, or a pharmaceutically acceptable salt thereof, is wherein R ⁷ , R ⁹ , and R ¹¹ are independently hydrogen, deuterium, alkyl, fluoro, or haloalkyl, R ^b , R ^e , and R ^b are a bond to L, and R ^c , R ^f , and R ¹ are independently hydrogen, alkyl, halo, alkoxy, alkoxyalkyl, or hydroxy.

25. In embodiment 25, the compound of any one of embodiments 1 A to 23, or a pharmaceutically acceptable salt thereof, is wherein R ⁷ , R ⁹ , and R ¹¹ are independently hydrogen, deuterium, alkyl, fluoro, or haloalkyl, R ^b , R ^e , and R ^b are independently hydrogen, alkyl, halo, alkoxy, alkoxyalkyl, hydroxy, -(alkylene) _n1 -OC(O)NR ¹³ R ^13a and R ^c , R ^f , and R ¹ are independently a bond to L.

26. In embodiment 26, the compound of any one of embodiments 1A to 23, or a pharmaceutically acceptable salt thereof, is wherein R ⁷ , R ⁹ , and R ¹¹ are independently a bond to L, R ^b , R ^e , and R ^b are independently hydrogen, alkyl, halo, alkoxy, alkoxyalkyl, hydroxy, or -(alkyl ene) _n i- OC(O)NR ¹³ R ^13a and R ^c , R ^f , and R ¹ are independently hydrogen, alkyl, halo, alkoxy, alkoxyalkyl, or hydroxy.

27. In embodiment 27, the compound of any one of embodiments 1A to 25, or a pharmaceutically acceptable salt thereof, is wherein R ⁷ , R ⁹ , and R ¹¹ are independently hydrogen, deuterium, methyl, ethyl, propyl, fluoro, difluoromethyl, or trifluoromethyl.

28. In embodiment 28, the compound of any one of embodiments 1A to 25, and 27, or a pharmaceutically acceptable salt thereof, is wherein R ⁷ , R ⁹ , and R ¹¹ are independently hydrogen.

29. In embodiment 29, the compound of any one of embodiments 1A to 25, and 27, or a pharmaceutically acceptable salt thereof, is wherein R ⁷ , R ⁹ , and R ¹¹ are independently deuterium.

30. In embodiment 30, the compound of any one of embodiments 1A to 25, or a pharmaceutically acceptable salt thereof, is wherein R ⁷ , R ⁹ , and R ¹¹ are independently alkyl, preferably methyl, ethyl, or propyl, preferably methyl.

31. In embodiment 31 , the compound of any one of embodiments 1 A to 25, and 27, or a pharmaceutically acceptable salt thereof, is wherein R ⁷ , R ⁹ , and R ¹¹ are independently fluoro.

32. In embodiment 32, the compound of any one of embodiments 1A to 25, or a pharmaceutically acceptable salt thereof, is wherein R ⁷ , R ⁹ , and R ¹¹ are independently haloalkyl, preferably fluoromethyl, difluoromethyl, or trifluoromethyl, preferably trifluoromethyl.

33. In embodiment 33, the compound of any one of embodiments 1A to 32, or a pharmaceutically acceptable salt thereof, is wherein R ⁸ , R ¹⁰ , and R ¹² are independently hydrogen, deuterium, alkyl, halo, haloalkyl, cyano, alkyloxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, phenyl, or heteroaryl.

34. In embodiment 34, the compound of any one of embodiments 1A to 33, or a pharmaceutically acceptable salt thereof, is wherein R ⁸ , R ¹⁰ , and R ¹² are independently hydrogen, deuterium, fluoro, methyl, cyano, methoxymethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, phenyl, pyrrolidinyl, furanyl, pyranyl, piperidinyl, morpholinyl, or 5- or 6- membereing heteroaryl (such as pyridyl, pyrimidinyl, or pyrazolyl).

35. In embodiment 35, the compound of any one of embodiments 1A to 34, or a pharmaceutically acceptable salt thereof, is wherein R ⁸ , R ¹⁰ , and R ¹² are independently hydrogen. 36. In embodiment 36, the compound of any one of embodiments 1A to 34, or a pharmaceutically acceptable salt thereof, is wherein R ⁸ , R ¹⁰ , and R ¹² are independently fluoro ormethyl.

37. In embodiment 37, the compound of any one of embodiments 1A to 34, or a pharmaceutically acceptable salt thereof, is wherein R ⁸ , R ¹⁰ , and R ¹² are independently hydrogen or cyano.

38. In embodiment 38, the compound of any one of embodiments 1A to 34, or a pharmaceutically acceptable salt thereof, is wherein R ⁸ , R ¹⁰ , and R ¹² are methoxymethyl.

39. In embodiment 39, the compound of any one of embodiments 1A to 34, or a pharmaceutically acceptable salt thereof, is wherein R ⁸ , R ¹⁰ , and R ¹² are independently cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropylethyl, cyclobutylethyl, or cyclopentylethyl.

40. In embodiment 40, the compound of any one of embodiments 1A to 34, or a pharmaceutically acceptable salt thereof, is wherein R ⁸ , R ¹⁰ , and R ¹² are phenyl, pyrrolidinyl, furanyl, pyranyl, piperidinyl, morpholinyl, or 5- or 6-membereing heteroaryl (such as pyridyl, pyrimidinyl, or pyrazolyl).

41. In embodiment 41, the compound of any one of embodiments 1 A to 23, or a pharmaceutically acceptable salt thereof, is wherein, independently of each other, R ⁷ andR ⁸ , R ⁹ and R ¹⁰ , and R ¹¹ and R ¹² 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 ^b are a bond to L, and R ^c , R ^f , and R ¹ are independently hydrogen, alkyl, halo, alkoxy, alkoxyalkyl, or hydroxy.

42. In embodiment 42, the compound of any one of embodiments 1A to 23, or a pharmaceutically acceptable salt thereof, is wherein, independently of each other, R ⁷ andR ⁸ , R ⁹ and R ¹⁰ , and R ¹¹ and R ¹² 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 ^b are independently hydrogen, alkyl, halo, alkoxy, alkoxyalkyl, hydroxy, -(alkylene) _n1 -OC(O)NR ¹³ R ^13a and R ^c , R ^f , and R ¹ are independently a bond to L.

43. In embodiment 43, the compound of any one of embodiments 1A to 23, 41, and 42, or a pharmaceutically acceptable salt thereof, is wherein R ⁷ and R ⁸ , R ⁹ and R ¹⁰ , and R ¹¹ and R ¹² together with the carbon atom to which they are attached form cyclopropyl, cyclobutylene, or cyclopentylene, each ring optionally substituted with methyl, fluoro, or methoxy. 44. In embodiment 44, the compound of any one of embodiments 1A to 23, 25 to 40, 42, and 43, or a pharmaceutically acceptable salt thereof, is wherein R ^b , R ^e , and R ^b are independently hydrogen, alkyl, halo, alkoxy, alkoxyalkyl, or hydroxy.

45. In embodiment 45, the compound of any one of embodiments 1A to 23, 25 to 40, and 42 to 44, or a pharmaceutically acceptable salt thereof, is wherein R ^b , R ^e , and R ^b are independently hydrogen, methyl, fluoro, methoxy, ethoxy, or methoxymethyl.

46. In embodiment 46, the compound of any one of embodiments 1A to 23, 25 to 40, and 42 to 45, or a pharmaceutically acceptable salt thereof, is wherein R ^b , R ^e , and R ^b are hydrogen.

47. In embodiment 47, the compound of any one of embodiments 1A to 23 and 25 to 45, or a pharmaceutically acceptable salt thereof, is wherein R ^b , R ^e , and R ^b are alkyl, preferably methyl.

48. In embodiment 48, the compound of any one of embodiments 1 A to 23 and 25 to 45, or a pharmaceutically acceptable salt thereof, is wherein R ^b , R ^e , and R ^b are halo, preferably fluoro.

49. In embodiment 49, the compound of any one of embodiments 1A to 23 and 25 to 45, or a pharmaceutically acceptable salt thereof, is wherein R ^b , R ^e , and R ^b are alkoxy, preferably methoxy or ethoxy.

50. In embodiment 50, the compound of any one of embodiments 1A to 23, 25 to 40, and 42 to 45, or a pharmaceutically acceptable salt thereof, is wherein R ^b , R ^e , and R ^b are alkoxyalkyl, preferably methoxymethyl.

51. In embodiment 51 , the compound of any one of embodiments 1 A to 23, 25 to 40, 42 and 43, or a pharmaceutically acceptable salt thereof, is wherein R ^b , R ^e , and R ^b are independently - ( alkyl ene)ni-OC(O)NR ¹³ R ^13a .

52. In embodiment 52, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, and 51, or a pharmaceutically acceptable salt thereof, is wherein nl is 0.

53. In embodiment 53, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, and 51, or a pharmaceutically acceptable salt thereof, is wherein nl is 1.

54. In embodiment 54, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, 51, and 53, or a pharmaceutically acceptable salt thereof, is wherein alkylene is methylene, ethylene, -CH(CH3)-, or -C(CH3)2-, preferably methylene.

55. In embodiment 55, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, and 51 to 54, or a pharmaceutically acceptable salt thereof, is wherein R ¹³ is hydrogen, deuterium, alkyl, deuterioalkyl, haloalkyl, haloalkoxyalkyl, or alkoxyalkyl and R ^13a 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.

56. In embodiment 56, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, and 51 to 55, or a pharmaceutically acceptable salt thereof, is wherein R ¹³ is hydrogen or deuterium.

57. In embodiment 57, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, and 51 to 55, or a pharmaceutically acceptable salt thereof, is wherein R ¹³ is alkyl.

58. In embodiment 58, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, and 51 to 55, or a pharmaceutically acceptable salt thereof, is wherein R ¹³ is haloalkyl.

59. In embodiment 59, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, and 51 to 55, or a pharmaceutically acceptable salt thereof, is wherein R ¹³ is haloalkoxyalkyl.

60. In embodiment 60, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, and 51 to 55, or a pharmaceutically acceptable salt thereof, is wherein R ¹³ is alkoxyalkyl.

61. In embodiment 61, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, and 51 to 55, or a pharmaceutically acceptable salt thereof, is wherein R ¹³ is deuterioalkyl.

62. In embodiment 62, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, and 51 to 61, or a pharmaceutically acceptable salt thereof, is wherein R ^13a is alkoxy.

63. In embodiment 63, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, and 51 to 61, or a pharmaceutically acceptable salt thereof, is wherein R ^13a is alkoxyalkyl.

64. In embodiment 64, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, and 51 to 61, or a pharmaceutically acceptable salt thereof, is wherein R ^13a is haloalkyl.

65. In embodiment 65, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, and 51 to 61, or a pharmaceutically acceptable salt thereof, is wherein R ^13a is haloalkoxyalkyl.

66. In embodiment 66, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, and 51 to 61, or a pharmaceutically acceptable salt thereof, is wherein R ^13a is cycloalkyl.

67. In embodiment 67, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, and 51 to 61, or a pharmaceutically acceptable salt thereof, is wherein R ^13a is deuterioalkyl.

68. In embodiment 68, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, and 51 to 61, or a pharmaceutically acceptable salt thereof, is wherein R ^13a is heterocyclyl substituted with Ri and R ^k independently selected from alkyl, halo, alkoxy, haloalkoxy, and haloalkyl. 69. In embodiment 69, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, and 51 to 68, or a pharmaceutically acceptable salt thereof, is wherein R ¹³ is hydrogen, methyl, methyl-d3, methoxyethyl, ethoxyethyl, or propoxyethyl; and R ^13a 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.

70. In embodiment 70, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, and 51 to 54, or a pharmaceutically acceptable salt thereof, is wherein R ¹³ and R ^13a 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 ^m , R ⁿ , R°, and R ^p and (b) bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiroheterocyclyl are independently substituted with R ^q , R ^r , and R ^s .

71. In embodiment 71, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, 51 to 54 and 70, or a pharmaceutically acceptable salt thereof, is wherein R ¹³ and R ^13a together with the nitrogen atom to which they are attached form heterocyclyl substituted with R ^m , R ⁿ , R°, and RP.

72. In embodiment 72, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, 51 to 54 and 70, or a pharmaceutically acceptable salt thereof, is wherein R ¹³ and R ¹⁴ 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 .

73. In embodiment 73, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, 51 to 54, 70, and 71, or a pharmaceutically acceptable salt thereof, is wherein R ¹³ and R ^13a together with the nitrogen atom to which they are attached form azetidin-l-yl, pyrrolidin- 1 -yl, piperidin- 1 -yl, piperazin-l-yl, morpholin-l-yl, or homomorpholin- 1 -yl, each ring substituted with R ^m , R ⁿ , R°, and R ^p .

74. In embodiment 74, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, 51 to 54, 70, 71, and 73, or a pharmaceutically acceptable salt thereof, is wherein R ¹³ and R ^13a together with the nitrogen atom to which they are attached form azetidin-l-yl, pyrrolidin- 1 -yl, piperidin- 1 -yl, piperazin-l-yl, morpholin-l-yl, or homomorpholin- 1 -yl, each ring substituted with R ^m , R ⁿ , R°, and R ^p where R ^m and R ⁿ are independently selected from hydrogen, deuterium, methyl, fluoro, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyano, or methoxy, R° is hydrogen, deuterium, methoxymethyl, or fluoro, and R ^p is hydrogen, deuterium, or fluoro. 75. In embodiment 75, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, 51 to 54, 70, 71, 73, and 74, or a pharmaceutically acceptable salt thereof, is wherein R ^m , R ⁿ , R°, and R ^p are hydrogen.

76. In embodiment 76, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, 51 to 54, 70, 71, 73, and 74, or a pharmaceutically acceptable salt thereof, is wherein R ¹³ and R ^13a together with the nitrogen atom to which they are attached form 3-methoxymethyl-azetidin-l-yl, 2- methoxymethyl-piperidin-l-yl, 3,3,4,4-tetrafluoropyrrolidin-l-yl, morpholin-l-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.

77. In embodiment 77, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, 51 to 54, 70, 71, and 73 to 76, or a pharmaceutically acceptable salt thereof, is wherein R ¹³ and R ^13a together with the nitrogen atom to which they are attached form morpholin-l-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.

78. In embodiment 78, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, 51 to 54, and 70, or a pharmaceutically acceptable salt thereof, is wherein R ¹³ and R ^13a together with the nitrogen atom to which they are attached form bicyclic heterocyclyl substituted with R ^q , R ^r , and R ^s .

79. In embodiment 79, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, 51 to 54, and 70, or a pharmaceutically acceptable salt thereof, is wherein R ¹³ and R ^13a together with the nitrogen atom to which they are attached form bridged heterocyclyl substituted with R ^q , R ^r , and R ^s .

80. In embodiment 80, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, 51 to 54, and 70, or a pharmaceutically acceptable salt thereof, is wherein R ¹³ and R ^13a together with the nitrogen atom to which they are attached form fused heterocyclyl substituted with R ^q , R ^r , and R ^s .

81. In embodiment 8q, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, 51 to 54, and 70, or a pharmaceutically acceptable salt thereof, is wherein R ¹³ and R ^13a together with the nitrogen atom to which they are attached form spiroheterocyclyl substituted with R ^q , R ^r , and

R ^s .

82. In embodiment 82, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, 51 to 54, and 70, or a pharmaceutically acceptable salt thereof, is wherein R ¹³ and R ^13a together with the nitrogen atom to which they are attached form a ring selected from: each ring substituted with R ^q , R ^r , and R ^s .

83. In embodiment 83, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, 70 and 78 to 82, or a pharmaceutically acceptable salt thereof, is wherein R ^s is hydrogen.

84. In embodiment 84, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, 70 and 78 to 83, or a pharmaceutically acceptable salt thereof, is wherein R ^r and R ^s are hydrogen.

85. In embodiment 85, the compound of any one of embodiments 1A to 23, 25 to 40, 42, 43, 70 and 78 to 84, or a pharmaceutically acceptable salt thereof, is wherein R ^q , R ^r , and R ^s (where applicable) are independently selected from hydrogen, methyl, methoxy, or fluoro.

86. In embodiment 86, the compound of any one of embodiments 1A to 24 and 26 to 85, or a pharmaceutically acceptable salt thereof, is wherein R ^c , R ^f , and R ¹ are hydrogen.

87. In embodiment 87, the compound of any one of embodiments 1A to 24 and 26 to 85, or a pharmaceutically acceptable salt thereof, is wherein R ^c , R ^f , and R ¹ are deuterium.

88. In embodiment 88, the compound of any one of embodiments 1A to 24 and 26 to 85, or a pharmaceutically acceptable salt thereof, is wherein R ^c , R ^f , and R ¹ are independently methyl, methoxy, methyloxy, chloro, or fluoro. 89. In embodiment 89, the compound of any one of embodiments 1A to 24 and 26 to 85, or a pharmaceutically acceptable salt thereof, is wherein R ^c , R ^f , and R ¹ are independently chloro or fluoro, preferably, R ^c , R ^f , and R ¹ are fluoro.

90. In embodiment 90, the compound of any one of embodiments 1A to 89, or a pharmaceutically acceptable salt thereof, is wherein Z is O.

91. In embodiment 91, the compound of any one of embodiments 1A to 90, or a pharmaceutically acceptable salt thereof, is wherein m and n are each 1 , or one of m and n is i and the other of m and n is 2.

92. In embodiment 92, the compound of any one of embodiments 1A to 90, or a pharmaceutically acceptable salt thereof, is wherein m and n are each 1 , or one of m and n is i.

93. In embodiment 93, the compound of any one of embodiments 1A to 90, or a pharmaceutically acceptable salt thereof, is wherein one of m and n is 1 and the other of m and n is 2.

94. In embodiment 94, the compound of any one of embodiments 1A to 90, or a pharmaceutically acceptable salt thereof, is wherein m and n are each 1.

95. In embodiment 95, the compound of any one of embodiments 1A to 90, or a pharmaceutically acceptable salt thereof, is wherein m is 1 and n is 3.

96. In embodiment 06, the compound of any one of embodiments 1A to 95, or a pharmaceutically acceptable salt thereof, is wherein R ¹ and R ^1a are independently selected from hydrogen, methyl, and ethyl, and R ^1b and R ^lc are hydrogen.

97. In embodiment 97, the compound of any one of embodiments 1A to 95, or a pharmaceutically acceptable salt thereof, is wherein R ¹ is cyanomethyl and R ^1a is hydrogen, methyl, or ethyl, preferably R ^1b is hydrogen, and R ^1b and R ^lc are hydrogen.

98. In embodiment 98, the compound of any one of embodiments 1A to 95, or a pharmaceutically acceptable salt thereof, is wherein R ¹ and R ^1a 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 ^1b and R ^lc are hydrogen.

99. In embodiment 99, the compound of any one of embodiments 1A to 95, or a pharmaceutically acceptable salt thereof, is wherein R ¹ and R ^1a 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 ^lc is hydrogen and R ^1b is attached to a carbon of the -(CH2) _Z - group and is alkylidenyl, preferably =CH2. 100. In embodiment 100, the compound of any one of embodiments 1A to 92, 94, and 98, or a pharmaceutically acceptable salt thereof, is wherein is: .

101. In embodiment 101, the compound of any one of embodiments 1A to 100, or a pharmaceutically acceptable salt thereof, is wherein R ⁵ is -Q-R ¹⁴ where Q is bond and R ¹⁴ is cycloalkyl, fused cycloalkyl, fused spirocycloalkyl, aryl, heteroaryl, or fused heteroaryl, wherein aryl, heteroaryl, and fused heteroaryl are substituted with R ^t R ^u , R ^v , and R ^w wherein R ^t and R ^u are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R ^v is hydrogen, alkenyl, alkynyl, cyanoalkenyl, cyanoalkynyl, or halo, and R ^w 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.

102. In embodiment 102, the compound of any one of embodiments 1A to 100, or a pharmaceutically acceptable salt thereof, is wherein R ⁵ is -Q-R ¹⁴ where Q is alkylene and R ¹⁴ is cycloalkyl, aryl, or fused heteroaryl, wherein aryl, fused heteroaryl, and heteroaryl are substituted with R ^t R ^u , R ^v , and R ^w wherein R ^t and R ^u are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R ^v is hydrogen, alkynyl, or halo, and R ^w 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.

103. In embodiment 103, the compound of any one of embodiments 1A to 100, or a pharmaceutically acceptable salt thereof, is wherein R ⁵ is -Q-R ¹⁴ where Q is -C(O)- and R ¹⁴ is cycloalkyl, aryl, fused heteroaryl, or heteroaryl, wherein aryl, fused heteroaryl and heteroaryl are substituted with R ^t R ^u , R ^v , and R ^w wherein R ^t and R ^u are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R ^v is hydrogen, alkynyl, or halo, and R ^w 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. 104. In embodiment 104, the compound of any one of embodiments 1 A to 101, or a pharmaceutically acceptable salt thereof, is wherein R ¹⁴ is cycloalkyl, fused cycloalkyl, aryl, or heteroaryl wherein aryl, and heteroaryl are substituted with R ^t R ^u , R ^v , and R ^w wherein R ^t and R ^u are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, haloalkoxy, hydroxy, alkoxy, heteroalkyl, hydroxyalkyl, amino, and cyano, R ^v is hydrogen, alkenyl, alkynyl, cyanoalkenyl, cyanoalkynyl, or halo, and R ^w 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.

105. In embodiment 105, the compound of any one of embodiments 1 A to 101, or a pharmaceutically acceptable salt thereof, is wherein R ⁵ is -Q-R ¹⁴ where Q is bond and R ¹⁴ is phenyl or naphthyl substituted with R ^t R ^u , R ^v , and R ^w .

105a. In embodiment 105a, the compound of embodiment 105, or a pharmaceutically acceptable salt thereof, is wherein R ^t and R ^u are independently selected from hydrogen, halo, and hydroxyl, R ^w is independently selected from hydrogen or halo, and R ^v is hydrogen or alkynyl.

105b. In embodiment 105b, the compound of embodiment 105, or a pharmaceutically acceptable salt thereof, is wherein R ¹⁴ is: , substituted with R ^t R ^u , and R ^w where R ^v is alkynyl.

105c. In embodiment 105c, the compound of embodiment 105, or a pharmaceutically acceptable salt thereof, is wherein R ¹⁴ is: , substituted with R ^t R ^u , and R ^w wherein R ^v is ethenyl.

106. In embodiment 122, the compound of any one of embodiments 1A to 101 and 105, or a pharmaceutically acceptable salt thereof, is wherein R ⁵ is -Q-R ¹⁴ where Q is bond and R ¹⁴ is phenyl or naphthyl substituted with R ^t R ^u , R ^v , and R ^w where R ^t and R ^u are independently selected from hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cycloalkyl, amino, cyano, and hydroxyalkyl, R ^v is hydrogen, fluoro, alkynyl, and R ^w 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.

107. In embodiment 107, the compound of any one of embodiments 1A to 105 and 106, or a pharmaceutically acceptable salt thereof, is wherein R ^t and R ^u independently selected from hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, difluoromethyl, trifluoromethoxy, hydroxy, methyl, ethoxy, cyclopropyl, amino, cyano, and hydroxymethyl, R ^v is hydrogen, ethynyl, 2- cyano vinyl, 2-cyanoethyn-l-yl, or fluoro, and R ^w is hydrogen, methyl, fluoro, amino, or cyclopropyl.

108. In embodiment 108, the compound of any one of embodiments 1A to 101, or a pharmaceutically acceptable salt thereof, is wherein R ⁵ is -Q-R ¹⁴ where Q is bond and R ¹⁴ is heteroaryl or fused heteroaryl substituted with R ^t R ^u , R ^v , and R ^w .

109. In embodiment 109, the compound of any one of embodiments 1A to 101 and 108, or a pharmaceutically acceptable salt thereof, is wherein R ⁵ is -Q-R ¹⁴ where Q is bond and R ¹⁴ is a monocyclic heteroaryl (e.g., pyridyl, pyrimidinyl, benzothiazolyl) substituted with R ^t R ^u , R ^v , and R ^w .

110. In embodiment 110, the compound of any one of embodiments 1A to 101 and 108, or a pharmaceutically acceptable salt thereof, is wherein R ⁵ is -Q-R ¹⁴ where Q is bond and R ¹⁴ is bicyclic heteroaryl (e,g, quinolinyl, isoquinolinyl, or indazolyl), substituted with R ^t R ^u , R ^v , and R ^w .

111. In embodiment 111, the compound of any one of embodiments 1A to 101 and 108 to

110, or a pharmaceutically acceptable salt thereof, is wherein the heteroaryl is substituted with R ^t R ^u , R ^v , and R ^w where R ^t and R ^u are independently selected from hydrogen, alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, cycloalkyl, amino, cyano, and hydroxyalkyl and R ^w 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 and R ^v is hydrogen.

112. In embodiment 112, the compound of any one of embodiments 1A to 101 and 108 to

110, or a pharmaceutically acceptable salt thereof, is wherein R ^t and R ^u are independently selected from hydrogen, methyl, ethyl, fluoro, chloro, trifluoromethyl, difluoromethyl, trifluoromethoxy, hydroxy, methyl, ethoxy, cyclopropyl, amino, cyano, and hydroxymethyl, R ^v is hydrogen or fluoro, and R ^w is hydrogen, methyl, fluoro, amino, or cyclopropyl.

113. In embodiment 113, the compound of any one of embodiments 1A to 101 and 104 to

112, or a pharmaceutically acceptable salt thereof, is wherein R ⁵ is -Q-R ¹⁴ where Q is bond and R ¹⁴ is: 113. In embodiment 113, the compound of any one of embodiments 1A to 101, 103-105, and 112, or a pharmaceutically acceptable salt thereof, is wherein R ⁵ is -Q-R ¹⁴ where Q is bond and R ¹⁴ is:

114. In embodiment 114, the compound of any one of embodiments 1A to 101, 103-105,

112, and 113, or a pharmaceutically acceptable salt thereof, is wherein R ⁵ is -Q-R ¹⁴ where Q is bond and R ¹⁴ is:

115. In embodiment 115, the compound of any one of embodiments 1 A to 114, or a pharmaceutically acceptable salt thereof, is wherein R ² is hydrogen, halo, or alkyl, and R ³ is hydrogen, halo, cycloalkyl, cycloalkyloxy, or alkyl.

116. In embodiment 116, the compound of any one of embodiments 1A to 115, or a pharmaceutically acceptable salt thereof, is wherein R ² and R ³ are each hydrogen.

117. In embodiment 117, the compound of any one of embodiments 1A to 115, or a pharmaceutically acceptable salt thereof, is wherein R ² is hydrogen or chloro and R ³ is hydrogen, fluoro, cyclopropyl, or cyclopropyloxy.

118. In embodiment 118, the compound of any one of embodiments 1 A to 115, or a pharmaceutically acceptable salt thereof, is wherein R ² is hydrogen and R ³ is fluoro or cyclopropyl.

119. In embodiment 119, the compound of any one of embodiments 1 A to 115 and 118, or a pharmaceutically acceptable salt thereof, is wherein R ² is hydrogen and R ³ is fluoro or cyclopropyl and R ³ is attached to C-8, the carbon substituted with R ⁵ being C-7.

120. In embodiment 120, the compound of any one of embodiments 1A to 119, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ligase ligand of formula (i): (i).

121. In embodiment 121, the compound of any one of embodiments 1A to 120, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ligase ligand of formula (i) is a group of formula (a):

122. In embodiment 122, the compound of any one of embodiments 1 A to 121, or a pharmaceutically acceptable salt thereof, is wherein R ²⁰ and R ²¹ are independently hydrogen or alkyl.

123. In embodiment 123, the compound of any one of embodiments 1A to 122, or a pharmaceutically acceptable salt thereof, is wherein R ²⁰ and R ²¹ are hydrogen.

124. In embodiment 124, the compound of any one of embodiments 1A to 122, or a pharmaceutically acceptable salt thereof, is wherein R ²⁰ is hydrogen and R ²¹ is methyl.

125. In embodiment 125, the compound of any one of embodiments 1 A to 121, or a pharmaceutically acceptable salt thereof, is wherein R ²⁰ and R ²¹ together with the carbon to which they are attached form >C=O.

126. In embodiment 126, the compound of any one of embodiments 1A to 120, or a pharmaceutically acceptable salt thereof, is wherein the ring A of the E3 ligase ligand of formula (i) is a group of formula (b):

127. In embodiment 127, the compound of any one of embodiments 1A to 120 and 126, or a pharmaceutically acceptable salt thereof, is wherein R ²² is hydrogen.

128. In embodiment 128, the compound of any one of embodiments 1A to 120 and 126, or a pharmaceutically acceptable salt thereof, wherein R ²² is alkyl, preferably methyl. 129. In embodiment 129, the compound of any one of embodiments 1A to 120, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ligase ligand of formula (i) is a group of formula (c): 130. In embodiment 130, the compound of any one of embodiments 1A to 128, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ligase ligand of formula (i) is:

131. In embodiment 131, the compound of any one of embodiments 1A to 128 and 130, or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ligase ligand of formula (i) is: 132. In embodiment 132, the compound of any one of embodiments 1A to 128, 130, and

131 , or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ligase ligand of formula (i) is:

132a. In embodiment 132a, the compound of any one of embodiments 1A to 128, 130, and

131 , or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ligase ligand of formula (i) is:

133. In embodiment 133, the compound of any one of embodiments 1A to 128, 130, and

131 , or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ligase ligand of formula (i) is:

134. In embodiment 134, the compound of any one of embodiments 1A to 128, 130, and

131 , or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ligase ligand of formula (i) is: 135. In embodiment 135, the compound of any one of embodiments 1A to 128, 130, and

131 , or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ligase ligand of formula (i) is:

136. In embodiment 136, the compound of any one of embodiments 1A to 128, 130, and

131 , or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ligase ligand of formula (i) is:

137. In embodiment 137, the compound of any one of embodiments 1A to 128, 130, and

131 , or a pharmaceutically acceptable salt thereof, is wherein ring A of the E3 ligase ligand of formula (i) is:

138. In embodiment 138, the compound of any one of embodiments 1A to 128, and 130 to 134, or a pharmaceutically acceptable salt thereof, is wherein R ^aa , R ^bb , R ^cc , and R ^dd are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy.

139. In embodiment 139, the compound of any one of embodiments 1 to 128, and 130 to 134, or a pharmaceutically acceptable salt thereof, is wherein R ^aa , R ^bb , R ^cc , and R ^dd are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and cyano.

140. In embodiment 140, the compound of any one of embodiments 1A to 128, 130 to 134, and 138, or a pharmaceutically acceptable salt thereof, is wherein R ^aa , R ^bb , R ^cc , and R ^dd are independently selected from hydrogen, methyl, methoxy, ethoxy, fluoro, trifluoromethyl, difluoromethyl, and trifluoromethoxy. 141. In embodiment 141, the compound of any one of embodiments 1A to 128, 130 to 134, and 138, or a pharmaceutically acceptable salt thereof, is wherein R ^aa , R ^bb , R ^cc , and R ^dd are independently selected from hydrogen and methyl.

142. In embodiment 142, the compound of any one of embodiments 1A to 128, 130 to 134, and 138, or a pharmaceutically acceptable salt thereof, is wherein R ^aa , R ^bb , R ^cc , and R ^dd are independently selected from hydrogen and methoxy.

143. In embodiment 143, the compound of any one of embodiments 1A to 128, 130 to 134, and 138, or a pharmaceutically acceptable salt thereof, is wherein R ^aa , R ^bb , R ^cc , and R ^dd are independently selected from hydrogen and fluoro.

143a. In embodiment 143a, the compound of any one of embodiments 1A to 128, 130 to 134, and 138, or a pharmaceutically acceptable salt thereof, is wherein R ^aa , R ^bb , R ^cc , and R ^dd are hydrogen.

144. In embodiment 144, the compound of any one of embodiments 1A to 128, 130 to 134, and 138, or a pharmaceutically acceptable salt thereof, is wherein R ^aa , R ^bb , R ^cc , and R ^dd are independently selected from hydrogen, trifluoromethyl, and difluoromethyl.

145. In embodiment 145, the compound of any one of embodiments 1A to 128, 130 to 134, and 138, or a pharmaceutically acceptable salt thereof, is wherein R ^aa , R ^bb , R ^cc , and R ^dd are independently selected from hydrogen and trifluoromethoxy.

146. In embodiment 146, the compound of any one of embodiments 1A to 128, 130 to 134, and 138, or a pharmaceutically acceptable salt thereof, is wherein R ^aa , R ^bb , R ^cc , and R ^dd are independently selected from hydrogen, fluoro, and trifluoromethyl.

146a. In embodiment 146a, the compound of any one of embodiments 1A to 146, or a pharmaceutically acceptable salt thereof, is wherein R ¹⁵ is hydrogen.

147. In embodiment 147, the compound of any one of embodiments 1A to 119, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ligase ligand of formula (ii):

(ii).

148. In embodiment 148, the compound of any one of embodiments 1A to 119 and 147, or a pharmaceutically acceptable salt thereof, is wherein Y ^a is CH. 149. In embodiment 149, the compound of any one of embodiments 1A to 119 and 147, or a pharmaceutically acceptable salt thereof, is wherein Y ^a is N.

150. In embodiment 150, the compound of any one of embodiments 1A to 119, and 147-

149, or a pharmaceutically acceptable salt thereof, is wherein Z ^a is a bond, -NH-, O, or -NHC(O)-.

151. In embodiment 152, the compound of any one of embodiments 1A to 119, and 147-

150, or a pharmaceutically acceptable salt thereof, is wherein Z ^a is a bond, -NH-, or -NHC(O)-.

152. In embodiment 152, the compound of any one of embodiments 1A to 119, and 147- 150, or a pharmaceutically acceptable salt thereof, is wherein Z ^a is a bond.

153. In embodiment 153, the compound of any one of embodiments 1A to 119, and 147- 150, or a pharmaceutically acceptable salt thereof, is wherein Z ^a is -NH-, or -NHC(O)-.

154. In embodiment 154, the compound of any one of embodiments 1A to 119, 147, 148, and 150, or a pharmaceutically acceptable salt thereof, is wherein Z ^a is -NH-.

154a. In embodiment 154a, the compound of any one of embodiments 1A to 119, and 147- 150, or a pharmaceutically acceptable salt thereof, is wherein Z ^a is -NHC(O)-.

155. In embodiment 155, the compound of any one of embodiments 1A to 119, and 147- 154a, or a pharmaceutically acceptable salt thereof, is wherein ring B is phenylene substituted with R ^ee and R ^ff independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

156. In embodiment 156, the compound of any one of embodiments 1A to 119, and 147- 154a, or a pharmaceutically acceptable salt thereof, is wherein ring B is cyclylaminylene substituted with R ^ee and R ^ff independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

157. In embodiment 157, the compound of any one of embodiments 1A to 119, and 147- 154a, or a pharmaceutically acceptable salt thereof, is wherein ring B is 5- or 6-membered monocyclic heteroarylene or a 9- or 10-membered fused bicyclic heteroarylene, wherein each heteroarylene ring contains one to three nitrogen ring atoms and each ring is substituted with R ^ee and R ^ff independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

158. In embodiment 158, the compound of any one of embodiments 1A to 119, 147-154a and 157, or a pharmaceutically acceptable salt thereof, is wherein ring B is 5- or 6-membered monocyclic heteroarylene containing one or two nitrogen ring atoms substituted with R ^ee and R ^ff independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

159. In embodiment 159, the compound of any one of embodiments 1A to 119, 147-150 and 157, or a pharmaceutically acceptable salt thereof, is wherein ring B is a 9- or 10-membered fused bicyclic heteroarylene containing one to three nitrogen ring atoms and substituted with R ^ee and R ^ff independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

160. In embodiment 160, the compound of any one of embodiments 1A to 119, 147-150 and 157, or a pharmaceutically acceptable salt thereof, is wherein ring B is a 9- or 10-membered fused bicyclic heteroarylene containing two nitrogen ring atoms and substituted with R ^ee and R ^ff independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

161. In embodiment 161, the compound of any one of embodiments 1A to 119 and 147 to 160, or a pharmaceutically acceptable salt thereof, is wherein the E3 ligase ligand of formula (ii) is:

162. In embodiment 162, the compound of any one of embodiments 1A to 119 and 147 to

161, or a pharmaceutically acceptable salt thereof, is wherein the E3 ligase ligand of formula (ii) is:

163. In embodiment 163, the compound of any one of embodiments 1A to 119, and 147 to

161, or a pharmaceutically acceptable salt thereof, is wherein the E3 ligase ligand of formula (ii) is:

164. In embodiment 164, the compound of any one of embodiments 1A to 119, and 147 to 163, or a pharmaceutically acceptable salt thereof, is wherein each R ^ee and R ^ff are independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, and haloalkoxy.

165. In embodiment 165, the compound of any one of embodiments 1A to 119, and 147 to 163, or a pharmaceutically acceptable salt thereof, is wherein R ^ee and R ^ff are independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, and cyano.

166. In embodiment 166, the compound of any one of embodiments 1A to 119, and 147 to 165, or a pharmaceutically acceptable salt thereof, is wherein R ^ee and R ^ff are independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, fluoro, chloro, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, or cyano.

167. In embodiment 167, the compound of any one of embodiments 1A to 119 and 147 to 165, or a pharmaceutically acceptable salt thereof, is wherein R ^ee and R ^ff are independently selected from hydrogen and methyl, ethyl, or isopropyl.

168. In embodiment A88, the compound of any one of embodiments 1A to 119 and 147 to 165, or a pharmaceutically acceptable salt thereof, is wherein R ^ee and R ^ff are independently selected from hydrogen and methoxy.

169. In embodiment 169, the compound of any one of embodiments 1A to 119 and 147 to 165, or a pharmaceutically acceptable salt thereof, is wherein R ^ee and R ^ff are independently selected from hydrogen, methyl, ethyl, isopropyl, chloro, and fluoro.

170 In embodiment 170, the compound of any one of embodiments 1A to 119 and 147 to 165, or a pharmaceutically acceptable salt thereof, is wherein one of R ^ee and R ^ff is hydrogen or fluoro and the other of R ^ee and R ^ff is selected from hydrogen, trifluoromethyl, 2,2,2-trifluoroethyl, and difluoromethyl.

171. In embodiment 171, the compound of any one of embodiments 1A to 119 147 to

163 and 164, or a pharmaceutically acceptable salt thereof, is wherein R ^ee and R ^ff are independently selected from hydrogen, difluoromethoxy, and trifluoromethoxy.

172. In embodiment 172, the compound of any one of embodiments 1A to 119 and 147 to 165, or a pharmaceutically acceptable salt thereof, is wherein R ^ee and R ^ff are independently selected from hydrogen, chloro, fluoro, and trifluoromethyl.

173. In embodiment A93, the compound of any one of embodiments 1A to 119 and 147 to 165, or a pharmaceutically acceptable salt thereof, is wherein R ^ee and R ^ff are independently hydrogen.

174. In embodiment 174, the compound of any one of embodiments 1A to 119 and 147 to 165, or a pharmaceutically acceptable salt thereof, is wherein R ^ee and R ^ff are independently chloro.

175. In embodiment 175, the compound of any one of embodiments 1A to 119 and 147 to 165, or a pharmaceutically acceptable salt thereof, is wherein R ^ee and R ^ff are independently fluoro.

176. In embodiment 176, the compound of any one of embodiments 1A to 119 and 147 to 165, or a pharmaceutically acceptable salt thereof, is wherein R ^ee and R ^ff are independently trifluoromethyl or 2,2,2-trifluoroethyl.

177. In embodiment 177, the compound of any one of embodiments 1 A to 119, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ligase ligand of formula (iii), (iv), (v), (vi), or (vii).

178. In embodiment 178, the compound of any one of embodiments 1A to 119 and 177, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ligase ligand of formula

(iii).

179. In embodiment 179, the compound of any one of embodiments 1A to 119 and 177, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ligase ligand of formula

(iv).

180. In embodiment 180, the compound of any one of embodiments 1A to 119 and 177, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ligase ligand of formula

(v). 181. In embodiment 181, the compound of any one of embodiments 1A to 119 and 177, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ligase ligand of formula

(vi).

181a. In embodiment 181a, the compound of any one of embodiments 1A to 119 and 177, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ligase ligand of formula

(vii).

181b. In embodiment 181b, the compound of any one of embodiments 1A to 119, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ligase ligand of formula

(viii).

181c. In embodiment 181c, the compound of any one of embodiments 1A to 119, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ligase ligand of formula (ix).

182. In embodiment 182, the compound of any one of embodiments 1A to 119, 177 to 180, and 181 c, or a pharmaceutically acceptable salt thereof, is wherein the Degron is an E3 ligase ligand of formula (iii), (iv), (v), or (ix), where R ¹⁷ , R ¹⁸ , and R ¹⁹ are 1 -fluorocycloprop- 1 -yl and W ^a is bond, S, or methylene.

183. In embodiment 183, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein X ¹ , X ² , X ³ , and X ⁴ are independently a bond.

184. In embodiment 184, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein X ¹ , X ² , X ³ , and X ⁴ are independently -alkylene-, preferably methylene.

185. In embodiment 185, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein X ¹ , X ² , X ³ , and X ⁴ are independently -O-.

186. In embodiment 186, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein X ¹ , X ² , X ³ , and X ⁴ are independently -(O- alkylene)-.

187. In embodiment 187, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein X ¹ , X ² , X ³ , and X ⁴ are independently -(alkylene-O)-.

188. In embodiment 188, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein X ¹ , X ² , X ³ , and X ⁴ are independently -(NR ^gg - alkylene)-. 189. In embodiment 189, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein X ¹ , X ² , X ³ . and X ⁴ are independently -(alkylene - NR ^hh )-.

190. In embodiment 190, the compound of any one of embodiments 1 to 176, or a pharmaceutically acceptable salt thereof, is wherein X ¹ , X ² , X ³ , and X ⁴ are

191. In embodiment 191, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein X ¹ , X ² , X ³ , and X ⁴ are -NH-.

192. In embodiment 192, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein X ¹ , X ² , X ³ , and X ⁴ are independently -N(alkyl)-.

193. In embodiment 193, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein X ¹ , X ² , X ³ , and X ⁴ are -C(=O)-.

194. In embodiment 194, the compound of any one of embodiments 1 to 176, or a pharmaceutically acceptable salt thereof, is wherein X ¹ , X ² , X ³ , and X ⁴ are independently - NRjJC(=O)-.

195. In embodiment 195, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein X ¹ , X ² , X ³ , and X ⁴ are independently - C(=O)NR ^kk -.

195a. In embodiment 195a, the compound of any one of embodiments 1A and 2 to 176, or a pharmaceutically acceptable salt thereof, is wherein X ¹ , X ² , X ³ , and X ⁴ are independently alkynylene.

195b. In embodiment 195b, the compound of any one of embodiments 1A and 2 to 176, or a pharmaceutically acceptable salt thereof, is wherein X ¹ , X ² , X ³ , and X ⁴ are independently -(alkylene)- heterocyclylene- or cycloalkylene,.

196. In embodiment 196, the compound of any one of embodiments 1A to 176, 188, 189, 194, and 195, or a pharmaceutically acceptable salt thereof, is wherein R ^gg , R ^hh , R ^jj , and R ^kk are independently hydrogen or alkyl.

197. In embodiment 197, the compound of any one of embodiments 1A to 196, or a pharmaceutically acceptable salt thereof, is wherein Z ⁶ is a bond or alkylene.

197a. In embodiment 197a, the compound of any one of embodiments 1A to 197, or a pharmaceutically acceptable salt thereof, is wherein Z ¹ is -alkylene-O-.

197al. In embodiment 197al, the compound of any one of embodiments 1A to 197, or a pharmaceutically acceptable salt thereof, is wherein Z ¹ is -methylene-O-. 197a2. In embodiment 197a2, the compound of any one of embodiments 1A to 197, or a pharmaceutically acceptable salt thereof, is wherein Z ¹ is -O-.

197b. In embodiment 197b, the compound of any one of embodiments 1A to 197a, or a pharmaceutically acceptable salt thereof, is wherein Z ² is -C(O)-.

197c. In embodiment 197c, the compound of any one of embodiments 1A to 197b, or a pharmaceutically acceptable salt thereof, is wherein Z ³ is -NR”-, or heterocyclene substituted with R ^ww and R ^xx .

197d. In embodiment 197d, the compound of any one of embodiments 1A to 197c, or a pharmaceutically acceptable salt thereof, is wherein R'™ and R ^xx are hydrogen.

197e. In embodiment 197e, the compound of any one of embodiments 1A to 197d, or a pharmaceutically acceptable salt thereof, is wherein R” is hydrogen. 197f. In embodiment 197f, the compound of any one of embodiments 1A to 197e, or a pharmaceutically acceptable salt thereof, is wherein Z ⁴ is a bond, alkylene, -(O-alkylene)c-, or -(alkylene-O)c-.

197g. In embodiment 197g, the compound of any one of embodiments 1A to 197f, or a pharmaceutically acceptable salt thereof, is wherein Z ⁵ is a bond, alkylene, -(O-alkylene)b-, or -(alkylene-O)b-.

197h. In embodiment 197h, the compound of any one of embodiments 1A to 197g, or a pharmaceutically acceptable salt thereof, is wherein Z ⁴ -Z ⁵ is a bond.

197i. In embodiment 197i, the compound of any one of embodiments 1A to 197h, or a pharmaceutically acceptable salt thereof, is wherein Z ⁶ is a bond, alkylene, -(O-alkylene)a-, or -(alkylene-O)a-.

197j . In embodiment 197j , the compound of any one of embodiments 1A to 197i, or a pharmaceutically acceptable salt thereof, is wherein a, b, c, and d is independently an integer selected from 1 to 3.

198. In embodiment 198, the compound of any one of embodiments 1A to 196, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is a bond, alkylene, or -alkylene-O-;

Z ² is a bond, -alkylene, -C(O)-, -C(O)NR-, phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with R'™ and R ^xx independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy; Z ³ is a bond, alkylene, -NR”-, -(O-alkylene)d-, -(alkylene-O)d-, phenylene, heteroarylene, heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R ^uu and R ^vv independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino;

Z ⁴ is a bond, alkylene, -C(O)NR-, -(O-alkylene)c-, or -(alkylene-O)c-;

Z ⁵ is a bond, alkylene, -C(O)-, -C(O)N(R)-, -NR’(CO)-, -(O-alkylene)b-, -(alkylene-O)b-, - 0(CH2) ₇ -, -O(CH2) ₈ -, or heterocyclylene, where each ring is substituted with R ^qq and R" independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy;

Z ⁶ is a bond, alkylene, -C(O)NR-, -NR’(CO)-, -S(O)2NR-, -NR’S(O)2-, -(O-alkylene)a-, - (alkylene-O)a-, phenylene, monocyclic heteroarylene, or heterocyclylene, where each ring is substituted with R ⁰⁰ and R ^pp independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy; and where each alkylene of -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ - is independently one to eight carbon atoms, R, R’ and R” is independently hydrogen or alkyl, each a, b, c, and d is independently an integer selected from 1 to 6, and each alkylene of -Z ¹ -, -Z ² -, -Z ³ -, -Z ⁴ -, -Z ⁵ - and

-Z ⁶ - is substituted with R ^yy and R ^zz where R ^yy is hydrogen or deuterium and R ^zz is hydrogen, deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocyclyl, aryl, or monocyclic heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and monocyclic heteroaryl are substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano

198. In embodiment 198, the compound of any one of embodiments 1A to 196, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is a bond, alkylene, or -alkylene-O-;

Z ² is a bond, -alkylene, -C(O)-, or -C(O)NR-;

Z ³ is a bond, alkylene, -NR”-, -(alkylene-O)d-, phenylene, heteroarylene, or heterocyclylene, where each ring is substituted with R ^uu and R ^vv independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino;

Z ⁴ is a bond, alkylene, -C(O)NR-, -(O-alkylene)c-, or -(alkylene-O)c-;

Z ⁵ is a bond, alkylene, -C(O)-, or heterocyclylene, where the ring is substituted with R ^qq and R" independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy;

Z ⁶ is a bond or alkylene; and where each alkylene of -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ - is independently one to eight carbon atoms, R, R’ and R” is independently hydrogen or alkyl, each a, b, c, and d is independently an integer selected from 1 to 6, and each alkylene of -Z ¹ -, -Z ² -, -Z ³ -, -Z ⁴ -, -Z ⁵ - and

-Z ⁶ - is substituted with R ^yy and R ^zz where R ^yy is hydrogen or deuterium and R ^zz is hydrogen, deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocyclyl, aryl, or monocyclic heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and monocyclic heteroaryl are substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

199. In embodiment 199, the compound of any one of embodiments 1A to 196, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -alkylene-O-;

Z ² is -C(O)NR-;

Z ³ , Z ⁴ and Z ⁵ is a bond; and

Z ⁶ is alkylene; and where each alkylene of -Z ¹ and -Z ⁶ - is independently one to eight carbon atoms, R is hydrogen or alkyl, and each alkylene of -Z ¹ - and -Z ⁶ - is substituted with R ^yy and R ^zz where R ^yy is hydrogen or deuterium and R ^zz is hydrogen, deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocyclyl, aryl, or monocyclic heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and monocyclic heteroaryl are substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

200. In embodiment 200, the compound of any one of embodiments 1A to 196, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -alkylene-O-;

Z ² is -C(O)NR-;

Z ³ is -(alkylene-O)d-;

Z ⁴ and Z ⁵ are bond and

Z ⁶ is alkylene; and where each alkylene of -Z ¹ -, -Z ³ -, and -Z ⁶ - is independently one to eight carbon atoms, R is hydrogen or alkyl, d is an integer selected from 1 to 6, and each alkylene of -Z ¹ -, -Z ³ -, and -Z ⁶ - is substituted with R ^yy and R ^zz where R ^yy is hydrogen or deuterium and R ^zz is hydrogen, deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocyclyl, aryl, or monocyclic heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and monocyclic heteroaryl are substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

201. In embodiment 201, the compound of any one of embodiments 1A to 196, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -alkylene-O-;

Z ² is -C(O)-;

Z ³ is heterocyclylene substituted with R ^uu and R ^vv independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino;

Z ⁴ and Z ⁵ are bond; and

Z ⁶ is alkylene; and where each alkylene of -Z ¹ - and -Z ² - is independently one to eight carbon atoms, and each alkylene of -Z ¹ - and -Z ² - is substituted with R ^yy and R ^zz where R ^yy is hydrogen or deuterium and R ^zz is hydrogen, deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocyclyl, aryl, or monocyclic heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and monocyclic heteroaryl are substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

202. In embodiment 202, the compound of any one of embodiments 1A to 196, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -alkylene-O-;

Z ² , Z ³ , Z ⁴ , and Z ⁵ are a bond;

Z ⁶ is alkylene; and where each alkylene of -Z ¹ - and -Z ⁶ - is independently one to eight carbon atoms, and each alkylene of -Z ¹ - and -Z ⁶ - is substituted with R ^yy and R ^zz where R ^yy is hydrogen or deuterium and R ^zz is hydrogen, deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocyclyl, aryl, or monocyclic heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and monocyclic heteroaryl are substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

203. In embodiment 203, the compound of any one of embodiments 1A to 196, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -alkylene-O-; Z ² is a bond;

Z ³ is -(alkylene-O)d-;

Z ⁴ and Z ⁵ is a bond;

Z ⁶ is alkylene; and where each alkylene of -Z ¹ -, -Z ² -, and -Z ⁶ - is independently one to eight carbon atoms.

204. In embodiment 204, the compound of any one of embodiments 1A to 196, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ are a bond; and

Z ⁶ is alkylene; and where alkylene of -Z ⁶ - is one to eight carbon atoms.

205. In embodiment 205, the compound of any one of embodiments 1A to 196, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is alkylene;

Z ² is -C(O)NR-;

Z ³ , Z ⁴ , and Z ⁵ are a bond;

Z ⁶ is alkylene; and where each alkylene of -Z ¹ - and -Z ⁶ - is independently one to eight carbon atoms, R is independently hydrogen or alkyl, and each alkylene of -Z ¹ - and -Z ⁶ - is substituted with R ^yy and R ^zz where R ^yy is hydrogen or deuterium and R ^zz is hydrogen, deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocyclyl, aryl, or monocyclic heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and monocyclic heteroaryl are substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

206. In embodiment 206, the compound of any one of embodiments 1A to 196, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is alkylene;

Z ² is a bond;

Z ³ is phenylene, heterocyclylene or heteroarylene, each ring substituted with R ^uu and R" independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino;

Z ⁴ and Z ⁵ is a bond;

Z ⁶ is alkylene; and where each alkylene of -Z ¹ - and -Z ⁶ - is independently one to eight carbon atoms, and each alkylene of -Z ¹ - and -Z ⁶ - is substituted with R ^yy and R ^zz where R ^yy is hydrogen or deuterium and R ^zz is hydrogen, deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocyclyl, aryl, or monocyclic heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and monocyclic heteroaryl are substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

207. In embodiment 207, the compound of any one of embodiments 1A to 196, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -alkylene-O-;

Z ² is a bond;

Z ³ is heterocyclylene substituted with R ^uu and R ^vv independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino;

Z ⁴ and Z ⁵ is a bond;

Z ⁶ or alkylene; and where each alkylene of -Z ¹ - and -Z ⁶ - is independently one to eight carbon atoms, and each alkylene of -Z ¹ - and -Z ⁶ - is substituted with R ^yy and R ^zz where R ^yy is hydrogen or deuterium and R ^zz is hydrogen, deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocyclyl, aryl, or monocyclic heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and monocyclic heteroaryl are substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

208. In embodiment 208, the compound of any one of embodiments 1A to 196, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is a bond, and

Z ⁶ is alkylene of one to eight carbon atom and the alkylene of -Z ⁶ - is substituted with R ^yy and R ^zz where R ^yy is hydrogen or deuterium and R ^zz is hydrogen, deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocyclyl, aryl, or monocyclic heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and monocyclic heteroaryl are substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

209. In embodiment 209, the compound of any one of embodiments 1A to 196, or a pharmaceutically acceptable salt thereof, is wherein: Z ¹ is -alkylene-O-;

Z ² is -C(0)-;

Z ³ is heterocyclylene substituted with R ^uu and R ^vv independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino;

Z ⁴ is or -(O-alkylene)c- or -(alkylene-O)c-;

Z ⁵ is a bond;

Z ⁶ is a bond or alkylene; and where each alkylene of -Z ¹ -, -Z ⁴ -, and -Z ⁶ - is independently one to eight carbon atoms, each c is independently an integer selected from 1 to 6, and each alkylene of -Z ¹ -, -Z ⁴ -, and -Z ⁶ - is substituted with R ^yy and R ^zz where R ^yy is hydrogen or deuterium and R ^zz is hydrogen, deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocyclyl, aryl, or monocyclic heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and monocyclic heteroaryl are substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

210. In embodiment 210, the compound of any one of embodiments 1A to 196, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -alkylene-O-;

Z ² is -C(O)-;

Z ³ is heterocyclylene substituted with R ^uu and R ^vv independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino;

Z ⁴ is alkylene;

Z ⁵ is heterocyclylene substituted with R ^qq and R ^rr independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy;

Z ⁶ is a bond or alkylene; and where each alkylene of -Z ¹ -, -Z ⁴ -, and -Z ⁶ - is independently one to eight carbon atoms, and each alkylene of -Z ¹ -, -Z ⁴ -, and -Z ⁶ - is substituted with R ^yy and R ^zz where R ^yy is hydrogen or deuterium and R ^zz is hydrogen, deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocyclyl, aryl, or monocyclic heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and monocyclic heteroaryl are substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

210a. In embodiment 210a, the compound of any one of embodiments 1A to 196, or a pharmaceutically acceptable salt thereof, is wherein:

Z' is O;

Z ² is alkylene;

Z ³ is phenylene (preferred p-phenylene)

Z ⁴ is monocyclic heteroarylene (preferred 1 ,4-triazolyl, 1,4-imidazolyl, 1,4-pyrazolyl, 1,4- pyrrolyl)

Z ⁵ and Z ⁶ are bond; and where each alkylene of -Z ³ - is independently one to eight carbon atoms, Ris independently hydrogen or alkyl, and alkylene of -Z ² - is substituted with R ^yy and R ^zz where R ^yy is hydrogen or deuterium and R ^zz is hydrogen, deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocyclyl, aryl, or monocyclic heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and monocyclic heteroaryl are substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano.

211. In embodiment 211, the compound of any one of embodiments 1 A to 210, or a pharmaceutically acceptable salt thereof, is wherein each alkylene of -Z ¹ -, -Z ² -, -Z ³ -, -Z ⁴ -, -Z ⁵ -, and - Z ⁶ - is independently selected from methylene, ethylene, propylene butylene, pentylene, or hexylene, preferably methylene, ethylene, or propylene.

212. In embodiment 212, the compound of any one of embodiments 1 A to 211, or a pharmaceutically acceptable salt thereof, is wherein each heterocyclylene of -Z ² -, -Z ³ -, -Z ⁴ -, -Z ⁵ -, and -Z ⁶ - is independently selected from azetidindiyl, pyrrolidindiyl, piperidindiyl, or piperazindiyl.

213. In embodiment 212, the compound of any one of embodiments 1 to 212, or a pharmaceutically acceptable salt thereof, is wherein each heterocyclylene of -Z ² -, -Z ³ -, -Z ⁴ -, -Z ⁵ -, and -Z ⁶ - is independently selected from 1,3- azetidindiyl, 1,3-pyrrolidindiyl, 1,4-piperidinyl, or 1,4- piperazindiyl.

214. In embodiment 214, the compound of any one of embodiments 1 A to 213, or a pharmaceutically acceptable salt thereof, is wherein each heteroarylene of -Z ² -, -Z ³ -, -Z ⁴ -, -Z ⁵ -, and - Z ⁶ - is independently selected from 2,4, or 3,5-pyridindiyl, 2,4, or 2,5-pyrimidindiyl, or 1,3, 1,4- pyrazoldiyl. 215. In embodiment 215, the compound of any one of embodiments 1 A to 214, or a pharmaceutically acceptable salt thereof, is wherein each alkylene of -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ -, as part of another group (e.g, -(O-alkylene)a, -(alkylene-O)a-, -(alkylene -NR”)-) and when present, is ethylene or propylene.

216. In embodiment 216, the compound of any one of embodiments 1A to 215, or a pharmaceutically acceptable salt thereof, is wherein each alkylene of -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ -, as part of another group (e.g, -(O-alkylene)a, -(alkylene-O)a-, -(alkylene -NR”)-) and when present, is ethylene.

217. In embodiment 217, the compound of any one of embodiments 1 to 216, or a pharmaceutically acceptable salt thereof, is wherein each R, R’ and R” of -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ -, when present, is independently hydrogen or methyl.

218. In embodiment 218, the compound of any one of embodiments 1A to 217, or a pharmaceutically acceptable salt thereof, is wherein each R, R’ and R” of -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ -, when present, is hydrogen.

219. In embodiment 219, the compound of any one of embodiments 1 A to 217, or a pharmaceutically acceptable salt thereof, is wherein each R, R’ and R” of -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ -, when present, is methyl.

220. In embodiment 220, the compound of any one of embodiments 1 A to 219, or a pharmaceutically acceptable salt thereof, is wherein phenylene of -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ -, when present, is independently selected from 1,3-phenylene and 1 ,4-phenylene unless stated otherwise in any of the embodiment above.

221. In embodiment 221, the compound of any one of embodiments 1A to 220, or a pharmaceutically acceptable salt thereof, is wherein heterocyclylene, bridged heterocyclylene, and spiro heterocyclylene, of -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ -, when present, are independently selected from

222. In embodiment 222, the compound of any one of embodiments 1 A to 221, or a pharmaceutically acceptable salt thereof, is wherein L (when the Degron is a group of formula (iii) to (vi)), -X'-L-, -X ² -L-, -X ³ -L- and -X ⁴ -L- are independently selected from: 223. In embodiment 223, the compound of any one of embodiments 1A to 222, or a pharmaceutically acceptable salt thereof, is wherein R ¹⁵ and R ¹⁶ are hydrogen.

224. In embodiment 224, the compound of any one of embodiments 1A to 196, or a pharmaceutically acceptable salt thereof, is wherein L is where:

Z ¹ is -alkylene-O; and

Z ² is -C(O)- or -C(O)NR-.

225. In embodiment 225, the compound of any one of embodiments 1A to 196 and 224, or a pharmaceutically acceptable salt thereof, is wherein Z ² is -C(O)- .

226. In embodiment 225, the compound of any one of embodiments 1A to 196 and 224, or a pharmaceutically acceptable salt thereof, is wherein Z ² is -C(O)NR-, preferably -CONH-.

227. In embodiment 227, the compound of any one of embodiments 1A to 182 and 225, or a pharmaceutically acceptable salt thereof, is wherein Z ³ is heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R ^uu and R ^vv independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, cyanoalkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, amino, alkylamino, and dialkylamino.

228. In embodiment 228, the compound of any one of embodiments 1 to 182 and 225, or a pharmaceutically acceptable salt thereof, is wherein Z ³ is heterocyclylene, bridged heterocyclylene, or spiro heterocyclylene, where each ring is substituted with R ^uu and R ^vv independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy amino, alkylamino, and dialkylamino.

229. In embodiment 229, the compound of any one of embodiments 1A to 182 and 226, or a pharmaceutically acceptable salt thereof, is wherein Z ³ is alkylene, alkynylene, -(alkylene -NR”)-, - (alkylene-O)a-, cycloalkylene, or spiro cyclolalkylene.

230. In embodiment 230, the compound of any one of embodiments 1A to 182 and 224 to

229, or a pharmaceutically acceptable salt thereof, is wherein Z ⁴ is a bond, alkylene, alkenylene, alkynylene, -NR’(CO)-, -O-, -(O-alkylene)c-, -(alkylene-O)c-, phenylene, or monocyclic heteroarylene, where each ring is substituted with R ^ss and R ^t independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy.

231. In embodiment 231 , the compound of any one of embodiments 1 A to 182 and 224 to

230, or a pharmaceutically acceptable salt thereof, is wherein Z ⁴ is a bond. 231a. In embodiment 231a, the compound of any one of embodiments 1A to 182 and 224 to 230, or a pharmaceutically acceptable salt thereof, is wherein Z ⁴ is alkylene.

23 lb. In embodiment 231b, the compound of any one of embodiments 1 A to 182 and 224 to 230, or a pharmaceutically acceptable salt thereof, is wherein Z ⁴ is alkynylene.

232. In embodiment 232, the compound of any one of embodiments 1A to 182 and 224 to 230, or a pharmaceutically acceptable salt thereof, is wherein Z ⁴ is -NR’(CO)-, -O-, -(O-alkylene)c-, - (alkylene-O)c-, phenylene, or monocyclic heteroarylene, where each ring is substituted with R ^ss and R ^t independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy.

233. In embodiment 233, the compound of any one of embodiments 1A to 182 and 224 to 230, or a pharmaceutically acceptable salt thereof, is wherein Z ⁴ is -O-.

234. In embodiment 234, the compound of any one of embodiments 1A to 182 and 224 to 230, or a pharmaceutically acceptable salt thereof, is wherein Z ⁴ is -(O-alkylene)c.

235. In embodiment 235, the compound of any one of embodiments 1A to 182 and 224 to 230, or a pharmaceutically acceptable salt thereof, is wherein Z ⁴ is -(alkylene-O)c.

236. In embodiment 236, the compound of any one of embodiments 1A to 182 and 224 to 230, or a pharmaceutically acceptable salt thereof, is wherein Z ⁴ is phenylene substituted with R ^ss and R ^t independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy.

237. In embodiment 237, the compound of any one of embodiments 1A to 182 and 224 to 230, or a pharmaceutically acceptable salt thereof, is wherein Z ⁴ is monocyclic heteroarylene substituted with R ^ss and R ^t independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy.

238. In embodiment 238, the compound of any one of embodiments 1A to 182 and 224 to

237, or a pharmaceutically acceptable salt thereof, is wherein Z ⁵ is a bond, alkylene, -SO2-, -NR’SO2-, -C(O)-, -NR’(CO)-, -(O-alkylene)b-, or -(alkylene-O)b-.

239. In embodiment 239, the compound of any one of embodiments 1A to 182 and 224 to

238, or a pharmaceutically acceptable salt thereof, is wherein Z ⁵ is a bond.

240. In embodiment 240, the compound of any one of embodiments 1A to 182 and 224 to 238, or a pharmaceutically acceptable salt thereof, is wherein Z ⁵ is a alkylene.

241. In embodiment 241, the compound of any one of embodiments 1A to 182 and 224 to 238, or a pharmaceutically acceptable salt thereof, is wherein Z ⁵ is a -SO2-. 242. In embodiment 242, the compound of any one of embodiments 1A to 182 and 224 to 238, or a pharmaceutically acceptable salt thereof, is wherein Z ⁵ is a -NR’SO ₂ -.

243. In embodiment 243, the compound of any one of embodiments 1A to 182 and 224 to 238, or a pharmaceutically acceptable salt thereof, is wherein Z ⁵ is -C(O)-.

244. In embodiment 244, the compound of any one of embodiments 1A to 182 and 224 to 238, or a pharmaceutically acceptable salt thereof, is wherein Z ⁵ is a -NR’(CO)-.

245. In embodiment 245, the compound of any one of embodiments 1A to 182 and 224 to 238, or a pharmaceutically acceptable salt thereof, is wherein Z ⁵ is a -(O-alkylene)b-.

246. In embodiment 246, the compound of any one of embodiments 1A to 182 and 224 to 238, or a pharmaceutically acceptable salt thereof, is wherein Z ⁵ is a -(alkylene-O)b.

247. In embodiment 247, the compound of any one of embodiments 1A to 182 and 224 to

246, or a pharmaceutically acceptable salt thereof, is wherein Z ⁶ is a bond, alkylene, -C(O)NR-, - NR’(CO)-, -(alkylene-O)a-, phenylene, heterocyclylene, bicyclic heterocyclylene, spiro heterocyclylene, -O-heterocyclylene-, or -heterocyclylene-C(O)-, where each ring is substituted with R ⁰⁰ and R ^pp independently selected from hydrogen, deuterium, alkyl, alkoxy, cyano, hydroxy, carboxy, halo, haloalkyl, and haloalkoxy.

248. In embodiment 248, the compound of any one of embodiments 1A to 182 and 224 to

247, or a pharmaceutically acceptable salt thereof, is wherein Z ⁶ is a bond.

249. In embodiment 249, the compound of any one of embodiments 1A to 182 and 224 to 247, or a pharmaceutically acceptable salt thereof, is wherein Z ⁶ is alkylene.

250. In embodiment 248, the compound of any one of embodiments 1A to 182 and 224 to 247, or a pharmaceutically acceptable salt thereof, is wherein Z ⁶ is a -C(O)NR-.

251. In embodiment 251, the compound of any one of embodiments 1A to 182 and 224 to 247, or a pharmaceutically acceptable salt thereof, is wherein Z ⁶ is -NR’(CO)-.

252. In embodiment 252, the compound of any one of embodiments 1A to 182 and 224 to 247, or a pharmaceutically acceptable salt thereof, is wherein Z ⁶ is a -(alkylene-O)a-.

253. In embodiment 253, the compound of any one of embodiments 1A to 182 and 224 to 247, or a pharmaceutically acceptable salt thereof, is wherein Z ⁶ is phenylene substituted with R ⁰⁰ and R ^pp independently selected from hydrogen, deuterium, alkyl, alkoxy, cyano, hydroxy, carboxy, halo, haloalkyl, and haloalkoxy. 254. In embodiment 254, the compound of any one of embodiments 1A to 182 and 224 to 247, or a pharmaceutically acceptable salt thereof, is wherein Z ⁶ is heterocyclylene substituted with R ⁰⁰ and R ^pp independently selected from hydrogen, deuterium, alkyl, alkoxy, cyano, hydroxy, carboxy, halo, haloalkyl, and haloalkoxy.

255. In embodiment 255, the compound of any one of embodiments 1A to 182 and 224 to 247, or a pharmaceutically acceptable salt thereof, is wherein Z ⁶ is bicyclic heterocyclylene substituted with R ⁰⁰ and R ^pp independently selected from hydrogen, deuterium, alkyl, alkoxy, cyano, hydroxy, carboxy, halo, haloalkyl, and haloalkoxy.

256. In embodiment 256, the compound of any one of embodiments 1A to 182 and 224 to 247, or a pharmaceutically acceptable salt thereof, is wherein Z ⁶ is spiro heterocyclylene substituted with R ⁰⁰ and R ^pp independently selected from hydrogen, deuterium, alkyl, alkoxy, cyano, hydroxy, carboxy, halo, haloalkyl, and haloalkoxy.

257. In embodiment 257, the compound of any one of embodiments 1A to 182 and 224 to 247, or a pharmaceutically acceptable salt thereof, is wherein Z ⁶ is -O-heterocyclylene- or - heterocyclylene-C(O)-, where each ring is substituted with R ⁰⁰ and R ^pp independently selected from hydrogen, deuterium, alkyl, alkoxy, cyano, hydroxy, carboxy, halo, haloalkyl, and haloalkoxy.

258. In embodiment 258, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -(alkylene-O)-;

Z ² is -C(O)NR;

Z ³ is alkylene, alkynylene, -(alkylene -NR”)-, or -(alkylene-O)a; and Z ⁴ , Z ⁵ , Z ⁶ , X ¹ , X ² , X ³ , and X ⁴ are a bond.

259. In embodiment 259, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -(alkylene-O)-;

Z ² is -C(O)-;

Z ³ is a heterocyclylene; and

Z ⁴ , Z ⁵ , Z ⁶ , X ¹ , X ² , X ³ , and X ⁴ are a bond.

259a. In embodiment 259a, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -(alkylene-O)-; Z ² is -C(0)-;

Z ³ is a heterocyclylene; and

Z ⁴ is alkylene, and

Z ⁵ , Z ⁶ , X ¹ , X ² , X ³ , and X ⁴ are a bond.

260. In embodiment 260, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -(alkylene-O)-;

Z ² is -C(O)NR-;

Z ³ is alkylene;

Z ⁶ is -C(O)NR- or heterocyclylene; and

Z ⁴ , Z ⁵ , X ¹ , X ² , X ³ , and X ⁴ are a bond.

260a. In embodiment 260a, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -(alkylene-O)-;

Z ² is -C(O)NR-;

Z ³ is alkylene; and

Z ⁴ , Z ⁵ , Z ⁶ , X ¹ , X ² , X ³ , and X ⁴ are a bond.

261. In embodiment 261, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -(alkylene-O)-;

Z ² is -C(O)-;

Z ³ is heterocyclylene or spiro heterocyclylene;

Z ⁶ is alkylene, -C(O)NR-, -(alkylene-O)a-, or phenylene; and

Z ⁴ , Z ⁵ , X ¹ , X ² , X ³ , and X ⁴ are a bond.

262. In embodiment 262, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -(alkylene-O)-;

Z ² is -C(O)-;

Z ³ is heterocyclylene;

Z ⁴ is alkynylene, phenylene, or -(alkylene-O) _c ; and

Z ⁵ , Z ⁶ , X ¹ , X ² , X ³ , and X ⁴ are a bond. 263. In embodiment 263, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -(alkylene-O)-;

Z ² is a -C(O)NR-;

Z ³ is a -(alkylene-O)a- or cycloalkylene;

Z ⁴ is alkylene or -O-; preferably -O-;

Z ⁶ is -C(O)NR- or - heterocyclylene; and

Z ⁵ , X ¹ , X ² , X ³ , and X ⁴ are a bond.

264. In embodiment 264, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -(alkylene-O)-;

Z ² is -C(O);

Z ³ is a heterocyclylene;

Z ⁴ is alkylene, -(O-alkylene)c, -O-, or heteroarylene;

Z ⁶ is -C(O)NR-, heterocyclylene, phenylene, -O-heterocyclylene, or -heterocyclylene-CO-; and

Z ⁵ , X ¹ , X ² , X ³ , and X ⁴ are a bond.

265. In embodiment 265, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -(alkylene-O)-;

Z ² is a -C(O)NR-;

Z ³ is alkylene, -(alkylene-O)i-3, cycloalkylene, or spiro cycloalkylene;

Z ⁵ is alkylene, NHCO, or -CO-;

Z ⁶ is -C(O)NR- or heterocyclylene; and

Z ⁴ , X ¹ , X ² , X ³ , and X ⁴ are a bond.

266. In embodiment 266, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -(alkylene-O)-;

Z ² is a -C(O); Z ³ is a heterocyclylene, spiro heterocyclylene, bridged heterocycylene, or heterocyclylene substituted with cyano, methoxy, methoxymethyl, hydroxymethyl, cyanomethyl, or 1 or 2 methyl;

Z ⁵ is CO or -(alkylene-O)1-3-;

Z ⁶ is heterocyclylene, bicyclic heterocycylene, spiro heterocycylene, -O- heterocyclylene, or heterocyclylene substituted with carboxy, cyano, hydroxy, methyl, methoxy, or fluoro; and

Z ⁴ , X ¹ , X ² , X ³ , and X ⁴ are a bond.

267. In embodiment 267, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -(alkylene-O)-;

Z ² is -C(O)-;

Z ³ is heterocyclylene;

Z ⁴ is alkylene or -O-alkylene-;

Z ⁵ is CO;

Z ⁶ is heterocyclylene; and

X ¹ , X ² , X ³ , and X ⁴ are a bond.

268. In embodiment 268, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -(alkylene-O)-;

Z ² is -C(O)NR-;

Z ³ is -(alkylene-O) 1-3;

X ¹ , X ² , X ³ , and X ⁴ are -alkyl ene-NH-; and

Z ⁴ , Z ⁵ , and Z ⁶ are bond.

269. In embodiment 269, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -(alkylene-O)-;

Z ² is -C(O)-;

Z ³ is a heterocyclylene or spiro heterocyclylene;

X ¹ , X ² , X ³ , and X ⁴ are -alkyl ene-NH-; and

Z ⁴ , Z ⁵ , and Z ⁶ are a bond. 270. In embodiment 270, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -(alkylene-O)-;

Z ² is -C(O)NR-;

Z ³ is heterocyclylene;

Z ⁵ is -C(O)-;

X ¹ , X ² , X ³ , and X ⁴ are cycloalkylene; and

Z ⁴ and Z ⁶ are a bond.

271. In embodiment 271, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -(alkylene-O)-;

Z ² is a -C(O)-;

Z ³ is a heterocyclylene;

Z ⁵ is NHCO, -NHSO2-, alkylene, -(O-alkylene)-, or C(O)-;

X ¹ , X ² , X ³ , and X ⁴ are -NH- or cycloalkylene; and

Z ⁴ and Z ⁶ are a bond.

272. In embodiment 272, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -(alkylene-O)-;

Z ² is -C(O)NR-;

Z ³ is a heterocyclylene;

Z ⁵ is CO or SO2;

Z ⁶ is phenylene;

X ¹ , X ² , X ³ , and X ⁴ are -alkyl ene-heterocycylene-; and

Z ⁴ is a bond.

273. In embodiment 273, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -(alkylene-O)-;

Z ² is -C(O);

Z ³ is heterocyclylene;

Z ⁵ is CO; 7 ⁶ is heterocyclylene;

X ¹ , X ² , X ³ , and X ⁴ are -NH- or O and Z ⁴ is a bond.

274. In embodiment 274, the compound of any one of embodiments 1A to 176, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -(alkylene-O)-;

Z ² is a -C(O);

Z ³ is heterocyclylene;

Z ⁴ is O;

Z ⁶ is heterocyclylene;

X ¹ , X ² , X ³ , and X ⁴ are alkynylene -; and Z ⁵ is a bond.

275. In embodiment 275, the compound of any one of embodiments 1A to 119 and 177 to 181b, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -(alkylene-O)-;

Z ² is -C(O)- or -CONH;

Z ³ is cycloalkylene, heterocyclylene, spiro heterocycylene, or alkylene; and Z ³ , Z ⁴ , Z ⁵ , X ¹ , X ² , X ³ , and X ⁴ are bond.

276. In embodiment 276, the compound of any one of embodiments 1A to 119 and 177 to 181b, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -(alkylene-O)-;

Z ² is -C(O)- or -CONH;

Z ³ is (alkylene-O)i-3, heterocyclylene, spiro heterocycylene, bridged heterocyclylene, or alkylene;

Z ⁴ is heteroarylene, alkylene, phenylene, or NHCO; and

Z ⁵ , Z ⁶ , X ¹ , X ² , X ³ , and X ⁴ are a bond.

277. In embodiment 277, the compound of any one of embodiments 1A to 119 and 177 to 181b, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -(alkylene-O)-;

Z ² is -C(O)- or -CONH;

Z ³ is heterocyclylene or alkylene; Z ⁶ is -heterocyclylene-CO-; and

Z ⁵ , Z ⁵ , X ¹ , X ² , X ³ , and X ⁴ are a bond.

278. In embodiment 278, the compound of any one of embodiments 1A to 119 and 177 to 181b, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -(alkylene-O)-;

Z ² is -C(O)-;

Z ³ is heterocyclylene;

Z ⁵ is alkylene or CO;

Z ⁶ is NHCO, alkylene, phenylene, or -heterocyclylene-CO-; and

Z ⁴ , X ¹ , X ² , X ³ , and X ⁴ are a bond.

279. In embodiment 279, the compound of any one of embodiments 1A to 119 and 177 to 181b, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -(alkylene-O)-;

Z ² is -C(O)NH-;

Z ³ is alkylene;

Z ⁴ is phenylene;

Z ⁵ is alkylene; -; and

Z ⁶ , X ¹ , X ² , X ³ , and X ⁴ are a bond.

280. In embodiment 280, the compound of any one of embodiments 1A to 119 and 177 to 181b, or a pharmaceutically acceptable salt thereof, is wherein:

Z ¹ is -(alkylene-O)-;

Z ² is -C(O)- or -CONH-;

Z ³ is heterocyclylene or alkylene;

Z ⁴ is alkylene;

Z ⁶ is heterocyclylene-CO or -NHCO—; and

Z ⁵ , X ¹ , X ² , X ³ , and X ⁴ are a bond.

281. In embodiment 281, the compound of any one of embodiments 224 to 280, or a pharmaceutically acceptable salt thereof, is wherein each alkylene of -Z ¹ -, -Z ³ -, -Z ⁴ -, -Z ⁵ -, and -Z ⁶ -, when present, is independently selected from methylene, ethylene, propylene butylene, pentylene, or hexylene, preferably methylene, ethylene, or propylene. 282. In embodiment 282, the compound of any one of embodiments 224 to 280, or a pharmaceutically acceptable salt thereof, is wherein each heterocyclylene of -Z ³ - and -Z ⁶ - is independently selected from azetidindiyl, pyrrolidindiyl, piperidindiyl, or piperazindiyl.

283. In embodiment 283, the compound of any one of embodiments 224 to 280, or a pharmaceutically acceptable salt thereof, is wherein each heterocyclylene of -Z ³ - and -Z ⁶ - is independently selected from 1,3- azetidindiyl, 1,3 -pyrrolidindiyl, 1 ,4-piperidinyl, or 1,4- piperazindiyl.

284. In embodiment 284, the compound of any one of embodiments 224 to 280, or a pharmaceutically acceptable salt thereof, is wherein each alkylene of -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ -, as part of another group (e.g, -(O-alkylene)a, -(alkylene-O)a-, -(alkylene -NR”)-) and when present, is ethylene or propylene.

285. In embodiment 285, the compound of any one of embodiments 224 to 280, or a pharmaceutically acceptable salt thereof, is wherein each alkylene of -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ -, as part of another group (e.g, -(O-alkylene)a, -(alkylene-O)a-, -(alkylene -NR”)-) and when present, is ethylene.

286. In embodiment 286, the compound of any one of embodiments 224 to 280, or a pharmaceutically acceptable salt thereof, is wherein each R, R’ and R” of -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ -, when present, is independently hydrogen or methyl.

287. In embodiment 287, the compound of any one of embodiments 224 to 280, or a pharmaceutically acceptable salt thereof, is wherein each R, R’ and R” of -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ -, when present, is hydrogen.

288. In embodiment 288, the compound of any one of embodiments 224 to 280, or a pharmaceutically acceptable salt thereof, is wherein each R, R’ and R” of -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ -, when present, is methyl.

289. In embodiment 289, the compound of any one of embodiments 224 to 280, or a pharmaceutically acceptable salt thereof, is wherein phenylene of -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ -, when present, is independently selected from 1,3-phenylene and 1 ,4-phenylene unless stated otherwise in any of the embodiments above.

290. In embodiment 290, the compound of any one of embodiments 224 to 280, or a pharmaceutically acceptable salt thereof, is wherein heterocyclylene, bridged heterocyclylene, and spiro heterocyclylene, of -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ -, when present, are independently selected from

291. In embodiment 291, the compound of any one of embodiments 224 to 280, or a pharmaceutically acceptable salt thereof, is wherein alkenylene of -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ -, when present, are independently selected from ethenylene, propenylene butenylene, pentyenylene, or hexenylene.

292. In embodiment 292, the compound of any one of embodiments 224 to 280, or a pharmaceutically acceptable salt thereof, is wherein alkynylene of -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ -, when present, are independently selected from ethynylene, propynylene butynylene, pentynylene, or hexynylene.

293. In embodiment 293, the compound of any one of embodiments 224 to 280, or a pharmaceutically acceptable salt thereof, is wherein cycloalkylene of -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ -, when present, are independently selected from cycloprolylene, cyclobutylene, cyclopentylene, cyclohexylene, and cycloheptylene.

294. In embodiment 294, the compound of any one of embodiments 224 to 280, or a pharmaceutically acceptable salt thereof, is wherein cycloalkylene of -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ -, when present are cyclohexylene.

295. In embodiment 295, the compound of any one of embodiments 224 to 280, or a pharmaceutically acceptable salt thereof, is wherein spiro cycloalkylene of -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ -, when present, are independently selected from spiro[5.5]undecanylene, spiro[4.5]decanylene, spiro[3.5]nonanylene, spiro[4.4]nonanylene, and spiro[3.4]octanylene. 296. In embodiment 296, the compound of any one of embodiments 224 to 280, or a pharmaceutically acceptable salt thereof, is wherein spiro cycloalkylene of -Z ¹ -Z ² -Z ³ -Z ⁴ -Z ⁵ -Z ⁶ -, when present, are spiro[5.5]undecanylene.

297. In embodiment 297, the compound of any one of embodiments 1 A to 119, or a pharmaceutically acceptable salt thereof, is wherein L-Degron is:

298. In embodiment 298, the compound of any one of embodiments 1A to 119, or a pharmaceutically acceptable salt thereof, is wherein L-Degron is:

299. In embodiment 299, the compound of any one of embodiments 1A to 196, or a pharmaceutically acceptable salt thereof, is wherein L is:

300. In embodiment 300, provided is a pharmaceutical composition comprising a compound of any one of embodiments 1A to 299, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

General Synthetic Scheme

Compounds Formula (IA) or (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 Suppiementals (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 (IA) or (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 °C to about 150 °C, such as from about 0 °C to about 125 °C and further such as at about room (or ambient) temperature, e.g., about 20 °C. Compounds of Formula (IA) or (I) can be prepared by methods known in the art. For example, compound of Formula (IA) or (I) where R ⁴ is -O-R ⁶ 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 with a suitable chlorination reagent such as POCh optionally in presence of a base such as DIPEA provides a 2,4-dichloro compound of formula 1-b. Compounds of formula l~a is either commercially available or they can be prepared by method well known in the art e.g., see Methods 1 and 2 below.

Method 1

Compounds of Formula 1-a where X ^a is halogen, U is CH, V is N, W is CH, R ² and R ³ 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 R ² and R ³ 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 tri chloroacetamido 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.

Method 2:

Compounds of Formula 1-a where X ^a is halogen, U, V and W are CH, R ² and R ³ are as defined in the Summary (or any embodiments thereof) can be by reacting a compound of formula 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 -chi oro-3 - fluorobenzoic acid, 2-amino-4-bromo-3 -fluorobenzoic acid and 2-amino-4-bromobenzoic acid are commercially available.

Treatment of compound 1-b with an amine of formula (a”) where m, n, R ¹ , R ^1a , R ^1b , and R ^lc 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 groups are as defined in Summary provides a compound of formula 1-d.

Amines of formula (a”) are either commercially available or can be made by methods known in the art. For example, benzyl 2-(cyanomethyl)piperazine-l -carboxylate, tert-butyl 2- (cyanomethyl)piperazine- 1 -carboxylate, benzyl 2,5-dimethylpiperazine-l -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 R ⁵ - M where R ⁵ 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 provides compound of formula 1-e.

Removal of amino protecting group PG in 1-e under standard reaction condition provides a compound of Formula (IA) or (I).

Alternatively, compounds of Formula (IA) or (I) where R ⁴ is -O-R ⁶ , 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

R ⁵ -M where R ⁵ 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 POCl ₃ 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 (IA) or (I) as described in Scheme 1 above.

NR" or heterocyclylene can be prepared by a precursor group of formula as illustrated and described in Scheme 3 below.

Treatment of a compound of formula 3-a (prepared by example 1 or 2) with a coulping agent such as CDI, and the like, treatment of the resulting intermediate with an amine of Z ³ -Z ⁴ -Z ⁵ -Z ⁶ - Degron precursor, provides a compound of formula 3-b which can the converted to compound of Formula (IA) or (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 (IA) or (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 (IA) or (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 fimgoides, 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 (IA) or (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 (IA) or (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 (IA) or (I) (unless stated otherwise, reference to compound/compounds of Formula (IA) or (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 (IA) or (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 (IA) or (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 (IA) or (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 (IA) or (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 (IA) or (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 (IA) or (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 (IA) or (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 (IA) or (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 (IA) or (I) may be administered topically, that is by non- systemic administration. This includes the application of a compound of Formula (IA) or (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 (IA) or (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 (IA) or (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 (IA) or (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 (IA) or (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 (IA) or (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 (IA) or (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 (IA) or (I) or a pharmaceutically acceptable salt thereof. When a compound of Formula (IA) or (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 (IA) or (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 (IA) or (I) or a pharmaceutically acceptable salt thereof. The combination therapy may also include therapies in which the compound of Formula (IA) or (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 (IA) or (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 (IA) or (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, W02016164675,W02016168540, WO2017015562, WO2017058728, WO2017058768, WO2017058792, W02017058805,W02017058807, W02017058902, WO2017058915, W02017070256, WO2017087528, W02017100546, WO20 17172979, 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;

S0S1 inhibitors including but not limited to BI 1701963 and BAY-293;

CSF1R inhibitors (PLX3397, LY3022855,) and CSF1R antibodies (IMC-054, RG7155);

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 (XALKOPJ® ; 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;

PI3 K inhibitors : 4- [2-( 1 H-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 trademark Avastin® by 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-ami nopropanoate, also known as BMS- 582664), motesanib (N-(2,3-dihydro-3,3- dimethyl-lH-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 tradename Nexavar®, CAS 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 tradename Sutent® by 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 Iressa®), N- [4- [(3 -chloro-4-fluorophenyl)amino] -7- [ [(3 S)-tetrahydro-3 - furanyl] oxy] -6- quinazolinyl]-4(dimethylamino)-2-butenamide, sold under the tradename Tovok® by Boehringer Ingelheim), cetuximab (sold under the tradename Erbitux® by Bristol-Myers Squibb), or panitumumab (sold under the tradename Vectibix® by Amgen);

HER2 receptor inhibitors: Trastuzumab (sold under the trademark Herceptin® by 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 trademark Tykerb® by 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 trademark Omnitarg®, by 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 trademarks Riuxan® and MabThera® by Genentech/Roche), tositumomab (sold under the trademarks Bexxar® by GlaxoSmithKline), or ofatumumab (sold under the trademark Arzerra® by GlaxoSmithKline);

Tyrosine kinase inhibitors: Erlotinib hydrochloride (CAS No. 183319-69-9, sold under the trademark Tarceva® by Genentech/Roche), Linifanib (N-[4-(3-amino-lH-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 tradename Sutent® by Pfizer), bosutinib (4-[(2,4-dichloro-5- methoxyphenyl)amino]-6- methoxy-7-[3-(4-methylpiperazin4-yl)propoxy]quinoline-3-carb onitrile, also known as SKI-606, and described in US Patent No. 6,780,996), dasatinib (CAS No. 302962-49- 8, sold under the tradename Sprycel® by Bristol-Myers Squibb), armala (CAS No. 444731-52-6, also known as pazopanib, sold under the tradename Votrient® by GlaxoSmithKline), imatinib (CAS No. 152459-95-5) and imatinib mesylate (CAS No. 220127-57-1) (sold under the tradenames Gilvec® and Gleevec® by Novartis);

DNA Synthesis inhibitors: Capecitabine (CAS No. 154361-50-9) (sold under the trademark Xeloda® by Roche), gemcitabine hydrochloride (CAS No. 122111-03-9) (sold under the trademark Gemzar® 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 tradenames Arranon® and Atriance® by G laxo SmithKline) ;

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

Human Granulocyte colony-stimulating factor (G-CSF) modulators: Filgrastim (sold under the tradename Neupogen® by Amgen);

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

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 Agrylin®);

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 trademark Aromasin® by Pfizer), letrozole (CAS No. 112809-51-5, sold under the tradename Femara® by Novartis), or anastrozole (CAS No. 120511-73-1, sold under the tradename Arimidex®);

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

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

16 and Etoposide phosphate, sold under the tradenames Toposar®, VePesid® and Etopophos®), or teniposide (CAS No. 29767-20-2, also known as VM-26, sold under the tradename Vumon®); mTOR inhibitors: Temsirolimus (CAS No. 162635-04-3, sold under the tradename Torisel® by 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 tradename Afmitor® by 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-2a inhibitors such as PT2977 (1672668-24-4), NKT2152, or PT2385 (CAS No. 1672665- 49-4); Osteoclastic bone resorption inhibitors: l-hydroxy-2-imidazol-l-yl-phosphonoethyl) phosphonic acid monohydrate (sold under the tradename Zometa® by Novartis);

CD33 Antibody Drug Conjugates: Gemtuzumab ozogamicin (sold under the tradename Mylotarg® 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 Zevalin®);

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

Synthetic Interleukin- 11 (IL-1 1): oprelvekin (sold under the tradename Neumega® by Pfizer/Wyeth);

Synthetic erythropoietin: Darbepoetin alfa (sold under the tradename Aranesp® by Amgen);

Receptor Activator for Nuclear Factor k B (RANK) inhibitors: Denosumab (sold under the tradename Prolia® by Amgen);

Thrombopoietin mimetic peptibodies: Romiplostim (sold under the tradename

Nplate® by Amgen;

Cell growth stimulators: Palifermin (sold under the tradename Kepivance® by Amgen);

Anti-insulin-like Growth Factor-1 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 Campath®);

Histone deacetylase inhibitors: Voninostat (sold under the tradename Zolinza® by Merck);

Alkylating agents: Temozolomide (sold under the tradenames Temodar® and Temodal® by Schering-Plough/Merck), dactinomycin (also known as actinomycin-D and sold under the tradename Cosmegen®), melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under the tradename Alkeran®), altretamine (also known as hexamethylmelamine (HMM), sold under the tradename Hexalen®), carmustine (sold under the tradename BiCNU®), bendamustine (sold under the tradename Treanda®), busulfan (sold under the tradenames Busulfex® and Myleran®), carboplatin (sold under the tradename Paraplatin®), lomustine (also known as CCNU, sold under the tradename CeeNU®), cisplatin (also known as CDDP, sold under the tradenames Platinol® and Platinol®-AQ), chlorambucil (sold under the tradename Leukeran®), cyclophosphamide (sold under the tradenames Cytoxan® and Neosar®), dacarbazine (also known as DTIC, DIC and imidazole carboxamide, sold under the tradename DTIC -Dome®), altretamine (also known as hexamethylmelamine (HMM) sold under the tradename Hexalen®), ifosfamide (sold under the tradename Ifex®), procarbazine (sold under the tradename Matulane®), mechlorethamine (also known as nitrogen mustard, mustine and mechloroethamine hydrochloride, sold under the tradename Mustargen®), streptozocin (sold under the tradename Zanosar®), thiotepa (also known as thiophosphoamide, TESPA and TSPA, sold under the tradename Thioplex®;

Biologic response modifiers: bacillus calmette-guerin (sold under the tradenames theraCys® and TICE® BCG), or Denileukin diftitox (sold under the tradename Ontak®);

Anti-tumor antibiotics: doxorubicin (sold under the tradenames Adriamycin® and Rubex®), bleomycin (sold under the tradename lenoxane®), daunorubicin (also known as dauorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, sold under the tradename Cerubidine®), daunorubicin liposomal (daunorubicin citrate liposome, sold under the tradename DaunoXome®), mitoxantrone (also known as DHAD, sold under the tradename Novantrone®), epirubicin (sold under the tradename Ellence™), idarubicin (sold under the tradenames Idamycin®, Idamycin PFS®), or mitomycin C (sold under the tradename Mutamycin®);

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

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

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

Heat Shock Protein (HSP) inhibitors: Tanespimycin (17-allylamino-17- 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 tradenames Promacta® and Revolade® by G laxo SmithKline) ;

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

Anti-androgens: Nilutamide (CAS No. 63612-50-0, sold under the tradenames Nilandron® and Anandron®), bicalutamide (CAS No. 90357-06-5, sold under tradename Casodex®), or flutamide (CAS No. 13311-84-7, sold under the tradename Fulexin™);

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

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-meth yl -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 tradenames Viadure® by Bayer AG, Eligard® by Sanofi-Aventis and Lupron® by Abbott Lab);

Taxane anti-neoplastic agents: Cabazitaxel (l-hydroxy-7,10 -dimethoxy-9-oxo-5,20- epoxytax-1 l-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)- 13-({ (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3- phenylpropanoyl}oxy)-l-hydroxy-9-oxo- 5,20-epoxy-7,19-cyclotax-l l-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: Cervarix® sold by GlaxoSmithKline, Gardasil® sold by Merck; Iron Chelating agents: Deferasinox (CAS No. 201530-41-8, sold under the tradename Exjade® by Novartis);

Anti -metabolites: Claribine (2-chlorodeoxyadenosine, sold under the tradename leustatin®), 5 -fluorouracil (sold under the tradename Adrucil®), 6-thioguanine (sold under the tradename Purinethol®), pemetrexed (sold under the tradename Alimta®), cytarabine (also known as arabinosylcytosine (Ara-C), sold under the tradename Cytosar-U®), cytarabine liposomal (also known as Liposomal Ara-C, sold under the tradename DepoCyt™), decitabine (sold under the tradename Dacogen®), hydroxyurea (sold under the tradenames Hydrea®, Droxia™ and Mylocel™), fludarabine (sold under the tradename Fludara®), floxuridine (sold under the tradename FUDR®), cladribine (also known as 2-chlorodeoxyadenosine (2-CdA) sold under the tradename Leustatin™), methotrexate (also known as amethopterin, methotrexate sodim (MTX), sold under the tradenames Rheumatrex® and Trexall™), or pentostatin (sold under the tradename Nipent®);

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

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

Plant Alkaloids: Paclitaxel protein-bound (sold under the tradename Abraxane®), vinblastine (also known as vinblastine sulfate, vincaleukoblastine and VLB, sold under the tradenames Alkaban- AQ® and Velban®), vincristine (also known as vincristine sulfate, LCR, and VCR, sold under the tradenames Oncovin® and Vincasar Pfs®), vinorelbine (sold under the tradename Navelbine®), or paclitaxel (sold under the tradenames Taxol and Onxal™);

Retinoids: Ali tretinoin (sold under the tradename Panretin®), tretinoin (all-trans retinoic acid, also known as ATRA, sold under the tradename Vesanoid®), Isotretinoin (13- cis-retinoic acid, sold under the tradenames Accutane®, Amnesteem®, Claravis®, Clarus®, Decutan®, Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®), or bexarotene (sold under the tradename Targretin®);

Glucocorticosteroids: Hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and sold under the tradenames Ala- Cort®, Hydrocortisone Phosphate, Solu-Cortef®, Hydrocort Acetate® and Lanacort®), dexamethazone ((8S, 9R, 10S, 1 IS, 13S,14S,16R, 17R)-9-fluoro-l 1,17-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-Cortel®, Orapred®, Pediapred® and Prelone®), prednisone (sold under the tradenames Deltasone®, Liquid Red®, Meticorten® and Orasone®), or methylprednisolone (also known as 6-Methylprednisolone, Methylprednisolone Acetate, Methylprednisolone Sodium Succinate, sold under the tradenames Duralone®, Medralone®, Medrol®, M-Prednisol® and Solu- Medrol®);

Cytokines: interleukin-2 (also known as aldesleukin and IL-2, sold under the tradename Proleukin®), interleukin- 11 (also known as oprevelkin, sold under the tradename Neumega®), alpha interferon alfa (also known as IFN-alpha, sold under the tradenames Intron® A, and Roferon-A®);

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

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

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

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

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

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, CD 137 (also known as 4-1BB), ICOS, A2AR, A2BR, HIF-2a, B7-H3, B7- H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, PD-1, 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, CD 137 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-1, 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-1, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP - 224. In some embodiments, the anti-PD-1 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- Ll, 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-Ll 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, INCAGNO 1949, 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 GV AX® (granulocytemacrophage 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-1 receptor antagonists: Casopitant (sold under the tradenames Rezonic® and Zunrisa® by GlaxoSmithKline); and Cytoprotective agents: Amifostine (sold under the tradename Ethyol®), 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 (References) and compounds of Formula (IA) or (I) (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.

Example 1

Synthesis ((3S,7aS)-7a-(((4-((lR,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- lH-pyrrolizin-3-yl)methyl 4-(2-((2-(2,6-dioxo piperidin-3-yl)-l ,3-dioxoisoindolin-4- yl)amino)ethyl)piperazine- 1 -carboxylate

Step 1 : (2S)-tert-butyl 2-(hydroxymethyl)-5-methoxypyrrolidine- 1 -carboxylate To a solution of (S)- 1 -tert-butyl 2-methyl 5-oxopyrrolidine-l,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 °C for 0.5 h, then at 20°C for 2 h. After cooling to 0 °C, methyl alcohol (3000 mL) and 2 M HC1 (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-l -carboxylate

To a solution of (2S)-tert-butyl 2-(hydroxymethyl)-5-methoxypyrrolidine-l -carboxylate (48.0 g, 208 mmol) in DCM (500 mL) at -70 °C was added TMSCN (51.5 g, 519 mmol, 64.9 mL) dropwise and then BF3.Et ₂ O (64.8 g, 457 mmol, 56.4 mL). The resulting mixture was then stirred at -70 °C for 1 h and then, then quenched with sat. NaHCO ₃ , 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-pyrrol idine-l -carboxylate

To a solution of tert-butyl (5 S)-2-cyano-5-(hydroxymethyl)pyrrolidine-l -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 °C. The mixture was stirred at 20 °C for 12 h and then quenched with H ₂ O, and extracted with EA. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , 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: (5 S)-l -tert-butyl 2-methyl 5-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine-l,2- dicarboxylate

A mixture of tert-butyl (2S)-2-[[tert-butyl(diphenyl)silyl]oxymethyl]-5-cyano-pyrrol idine-l- 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 °C for 12 h under N2 atmosphere. The mixture was acidified with 1.0 M HC1 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 (5 S)- 1 -tert-butyl 2-methyl 5-(((tert-butyldiphenylsilyl)oxy)methyl)- pyrro li dine- 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 °C and the mixture was stirred at -70 °C for 15 min. 3-Chloro-2- (chloromethyl)prop-l-ene (4.52 g, 36.1 mmol, 4.19 mL, 1.5 eq) was added dropwise at -70 °C under nitrogen atmosphere and the resulting mixture was stirred 16 h at 20 °C. The mixture was quenched with sat. NaHCO ₃ , 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-methylen etetrahydro-lH- 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-l,2-dicarboxylate (10.7 g, 18.2 mmol, 1 eq) in DCM (90 mL) was added TFA (45 mL) at 0 °C and the resulting mixture was stirred at 20 °C for 2 h. The reaction was quenched by adding sat. aq. NaHCO ₃ solution at 0 °C 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-methyle netetrahydro-lH-pyrrolizin-

7 a(5H)-yl)methanol

To a solution of LiA1H ₄ (540 mg, 14.2 mmol, 2 eq) in THF (20 mL) was added dropwise methyl (5S,7aS)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-methylen etetrahydro-lH-pyrrolizine- 7a(5H)-carboxylate (3.2 g, 7.12 mmol, 1 eq) in THF (10 mL) at -40 °C and the resulting mixture was stirred at -40 °C for 1 h. After cooling the mixture to 0 °C, 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).

Step 8: (lR,5S)-tert-butyl 3 -(2-(((5S,7aS)-5 -(((tert-butyl diphenylsilyl)oxy) methyl)-2-methylene- hexahydro-lH-pyrrolizin-7a-yl)methoxy)-7-chloro-8-fluoropyri do[4,3-d] pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

To a solution of ((5S,7aS)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-methyle ne-hexahydro- lH-pyrrolizin-7a-yl)methanol (886 mg, 2.10 mmol, 1.0 eq) in THF (1.0 mL) was added NaH (168.1 mg, 4.20 mmol, 60% in mineral oil, 2.0 eq) in an ice water bath, followed by (lR,5S)-tert-butyl 3- (2,7-dichloro-8-fluoropyrido[4,3-d] pyrimidin-4-yl)-3,8-diazabicyclo-[3.2.1]octane-8-carboxylate (900 mg, 2.10 mmol, 1.0 eq). The resulting mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched with water at 5 °C, and then extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by column chromatography, eluted with DCM/MeOH (0-10%), to give the title compound (1.3 g). Step 9: (lR,5S)-tert-butyl 3-(2- (((5S,7aS)-5-(((tert-butyldiphenylsilyl)oxy) methyl)-2-methylenehexahydro-lH-pyrrolizin-7a- yl)methoxy)-8-fluoro-7-(7-fluoro-3-(methoxy methoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-l- yl)pyrido [4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo-[3.2.1]octane-8-carb oxylate

A mixture of (lR,5S)-tert-butyl 3-(2-(((5S,7aS)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2- methylenehexahydro-lH-pyrrolizin-7a-yl) methoxy)-7-chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1] octane-8-carboxylate (1.2 g, 1.48 mmol, 1.0 eq), ((2-fluoro-6- (methoxymethoxy)-8-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2 -yl)naphthalen-l-yl)ethynyl)- triisopropylsilane (986 mg, 1.62 mmol, 1.1 eq), cataCXiumAPdG3 (110.3 mg, 0.15 mmol, 0.1 eq), K2CO3 (610.7 mg, 4.43 mmol, 3.0 eq) in DME (9.0 mL) and H2O (3.00 mL) was stirred at 85 °C for 5 h under N2 atmosphere. The mixture was filtered and concentrated, and the residue was purified by column chromatography, eluted with EtOAc/PE (0-30%), to give the title compound (1.6 g). Step 10: (lR,5S)-tert-butyl 3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy) naphthal en-l-yl)-8-fluoro- 2-(((5S,7aS)-5-(hydroxymethyl)-2-methylene hexahydro- lH-pyrrolizin-7a-yl)methoxy)pyrido[4, 3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] octane-8-carboxylate

To a solution of (lR,5S)-tert-butyl 3-(2-(((5S,7aS)-5-(((tert-butyldiphenylsilyl)oxy)-methyl)- 2-methylenehexahydro-lH-pyrrolizin-7a-yl) methoxy)-8-fluoro-7-(7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl) naphthalen-l-yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1.6 g, 1.38 mmol, 1.0 eq) in THF (10.0 mL) was added TBAF (1.0 M, 6.9 mL, 5.0 eq) and the resulting mixture was stirred at rt for 3 h. After cooling in an ice-water bath, the mixture was quenched by adding water and then extracted with EtOAc. The combined organic layers were dried over Na2 SO4, filtered and concentrated. The residue was purified by column chromatography, eluted with DCM/MeOH (0-5%), to give the title compound (980 mg). Step 10: tert-butyl (lR,5S)-3-(7-(8-ethynyl-7-fluoro-3 -(methoxymethoxy) naphthal en-l-yl)-8-fluoro-

2-(((5S,7aS)-2-methylene-5-((((4-nitrophenoxy) carbonyl)oxy)methyl)tetrahydro-lH-pyrrolizin-

7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazab icyclo[3.2.1]octane-8-carboxylate

To a solution of tert-butyl (lR,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy) naphthalen- l-yl)-8-fluoro-2-(((5S,7aS)-5-(hydroxymethyl)-2-methylene tetrahydro- 1 H-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2 . l]octane-8-carboxylate (50 mg, 0.07 mmol) in anhydrous THF (1.5 mL) at 0 °C was added triethylamine (0.09 mL, 0.65 mmol), followed by 4-nitrophenyl carbonochloridate (65.62 mg, 0.33 mmol) under argon atmosphere. The resulting mixture was gradually warmed to rt and stirred for 18 h. Additional 2.0 eq of (4-nitrophenyl) carbonochloridate (26.249 mg, 0.1302 mmol) was added and the mixture was stirred for 40 h. Water was then added and the mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated to afford title compound (60 mg). Step 11: tert-butyl (lR,5S)-3-(2-(((5S,7aS)-5-(((4-(2-((2-(2,6-dioxopiperidin-3- yl)-l,3- dioxoisoindolin-4-yl)amino)ethyl)piperazine- 1 -carbonyl)oxy)methyl)-2-methylenetetrahydro- 1 H- pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(metho xymethoxy)naphthalen-l-yl)-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oc tane-8-carboxylate

A mixture of tert-butyl (lR,5S)-3-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthale n-l- yl)-8-fluoro-2-(((5S,7aS)-2-methylene-5-((((4-nitro phenoxy)carbonyl)oxy)methyl)tetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3, 8-diazabicyclo[3.2.1]octane-8- carboxylate (50 mg, crude) and 4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopipe ridin- 3-yl)isoindoline-l,3-dione (prepared as described in J Med. Chem. 2022, 65, 13, 9096-9125) (61.90 mg, 0.16 mmol, 3.0 eq), and TEA (43.26 mg, 0.43 mmol, 8.0 eq) in THF (1 mL) was stirred at 25°C for 3 hrs under N2. The reaction mixture was quenched with sat. NaHC'O, aq. solution and then extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue obtained was purified by flash chromatography, eluted with DCM/MeOH (0-5%) to afford the title compound (8 mg).

Step 12: ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl) -6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl 4-(2-((2-(2,6-dioxopiperi din-3 -yl)- 1,3 -di oxoisoindolin-4- yl)amino)ethyl)piperazine- 1 -carboxylate

To a solution of tert-butyl (lR,5S)-3-(2-(((5S,7aS)-5-(12-((2-(2,6-dioxopiperidin-3-yl)- l,3- dioxoisoindolin-4-yl)amino)-3 -oxo-2, 7,10-trioxa-4-azadodecyl)-2-methylenetetrahydro- 1H- pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethynyl-7-fluoro-3-(metho xymethoxy)naphthalen-l-yl)-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oc tane-8-carboxylate (8 mg, 6.8 pmol) in DCM (1.0 mL) was added a solution of HC1 in dioxane (4.0 M, 0.5 mL) at 5 °C and the resulting mixture was stirred at 5 °C for 3 hs. The mixture was concentrated in reduced pressure and the residue was basified to pH = 8 by adding a solution of ammonia in MeOH. After volatiles were removed under reduced pressure, the residue was purified by HPLC to afford the title compound (2.7 mg). MS (ES, m/z): [M+H] ⁺ =1036.3.

Example 2

Synthesis ((3S,7aS)-7a-(((4-((lR,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- lH-pyrrolizin-3-yl)methyl (2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4 - yl)amino)ethoxy)ethoxy)ethyl) carbamate

The title compound was prepared by proceeding analogously as described in Example 1 , Steps 11 and 12, using 4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopipe ridin-3-yl)isoindoline- 1,3-dione (ref. J. Med. Chem. 2019, 62, 448 - 466) instead of 4-((2-(2-(2- aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)i soindoline- 1,3-dione in Step 11. MS (ES, m/z): [M+H] ⁺ =1055.4.

Example 3

Synthesis ((3S,7aS)-7a-(((4-((lR,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- lH-pyrrolizin-3-yl)methyl (5-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)pentyl)carbamate

The title compound was prepared by proceeding analogously as described in Example 1 , Steps 11 and 12, using 4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopipe ridin-3- yl)isoindoline- 1,3-dione (ref. J. Med. Chem. 2019, 62, 448 - 466) instead of 4-((2-(2-(2- aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)i soindoline- 1,3-dione in Step 11. MS (ES, m/z): [M+H] ⁺ =1009.4.

Example 4

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl (8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)am ino)-8-

Step 1: tert-butyl (8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)am ino)-8- oxooctyl)carbamate

A mixture of 5-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-l, 3-dione (200 mg, 0.73 mmol) and 8-((tert-butoxycarbonyl)amino)octanoic acid (227.79 mg, 0.88 mmol) in anhydrous N,N- Dimethylformamide (4 mL) was added 1 -methylimidazole (420.64 mg, 5.12 mmol), followed by chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (616.1 mg, 2.2 mmol) at 25 °C for 3 h under argon atmosphere and stirred. The mixture was dissolved in water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate. After filtration, the filtrate was concentrated under reduced pressure. The residue obtained was purified by Prep-HPLC (0~70% acetonitrile in water with 0.05% formic acid) to afford title compound (200 mg, 0.3887 mmol, 53.102% yield) as an off-white solid.

Step 2: 8-amino-N-(2-(2,6-dioxopiperidin-3-yl)-l ,3-dioxoisoindolin-5-yl)octanamide hydrochloride

To a stirred solution of tert-butyl (8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)-8-oxooctyl)carbamate (50 mg, 0.0972 mmol) in anhydrous dichloromethane (1 mL) was added 4M hydrogen chloride in dioxane (0.5 mL) at 0 °C and the mixture was stirred for 1 h. The solvent was removed under reduced pressure to afford title compound (40 mg, 0.0887 mmol, 91.29% yield) as a white solid, which was used to next step directly without further purification.

Step 3: ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy) methyl)-6-methylene-hexahydro- lH-pyrrolizin-3-yl)methyl (8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)am ino)-8- oxooctyl)carbamate

The title compound was prepared by proceeding analogously as described in Example 1 , Steps

11 and 12, using 8-amino-N-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5 -yl)octanamide hydrochloride instead of 4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopipe ridin-3- yl)isoindoline- 1,3-dione in Step 11. LCMS (ESI) m/z [M+H] ⁺ = 1065.

Example 5

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl (8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)am ino)-8- oxooctyl)carbamate

The title compound was prepared by proceeding analogously as described in Example 1 , Steps 11 and 12, using 8-amino-N-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4 -yl)octanamide hydrochloride (ref: WO2021/201577) instead of 4-((2-(2-(2-aminoethoxy)ethoxy)-ethyl)amino)-2- (2, 6-dioxopiperidin-3-yl)isoindoline-l, 3-dione in Step 11. LCMS (ESI) m/z [M+H] ⁺ = 1065.

Example 6

Synthesis of ((3R,7aR)-7a-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-e thynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl (2-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindoli n-5-yl)amino)- 3-oxopropoxy)ethoxy)ethoxy)ethyl)carbamate

The title compound was prepared by proceeding analogously as described in Example 4, Steps 1-3, using 2,2-dimethyl-4-oxo-3,8,l l,14-tetraoxa-5-azaheptadecan- 17-oic acid instead of 8-((tert- butoxycarbonyl)amino)octanoic acid in Step 1. LCMS (ESI) m/z [M+H] ⁺ = 1126.3.

Example 7

Synthesis of ((3S,7aS)-7a-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-e thynyl-7-fluoro-3- hydroxynaphthalen- 1 -yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy) methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl (4-((2-(2,6-dioxo piperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)butyl)carbamate

The title compound was prepared by proceeding analogously as described in Example 1 , Steps 11 and 12, using 5-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoli ne-l, 3-dione (ref: WO2021/155321) instead of 4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopipe ridin-3- yl)isoindoline- 1,3-dione in Step 1. LCMS (ESI) m/z [M+H] ⁺ = 995.3.

Example 8

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl (3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)am ino)-3- oxopropyl)(methyl) carbamate

Step 1 : tert-butyl (3-((2-(2,6-dioxopiperidin-3-yl)-l ,3-dioxoisoindolin-5-yl)amino)-3-oxopropyl)- (methyl)carbamate

To a solution of 3- [tert-butoxycarbonyl (methyl)amino]propanoic acid (89.25 mg, 0.44 mmol) and 5-amino-2-(2,6-dioxo-3-piperidyl)isoindoline-l, 3-dione (100 mg, 0.37 mmol) in anhydrous DMF (2 mL) was added NMI (210.32 mg, 2.56 mmol), followed by TCFH (308.05 mg, 1.1 mmol) at 25 °C under argon atmosphere and the reaction mixture was stirred for 2 h at rt. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue obtained was purified by Prep-HPLC (0~50% acetonitrile in water with 0.05% formic acid) to afford the title compound (100 mg).

Step 2: N-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-3-( methylamino)propanamide

To a stirred solution of tert-butyl N-[3-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5- yl]amino]-3-oxo-propyl]-N-methylcarbamate (50 mg, 0.11 mmol) in DCM (1 mL) was added 4M HC1 in dioxane (0.5mL) at 0 °C and the reaction mixture was stirred for 1 h. The solvent was removed under reduced pressure to afford the title compound (43 mg).

Step 3: ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl (3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)am ino)-3- oxopropyl)(methyl)carbamate

The title compound was prepared by proceeding analogously as described in Example 1 , Steps 11 and 12, using N-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)-3-( methylamino) propenamide instead of 4-((2-(2-(2-aminoethoxy)ethoxy)-ethyl)amino)-2-(2,6-dioxopip eridin-3- yl)isoindoline- 1,3-dione in Step 11. MS (ES, m/z): [M+H] ⁺ = 1009.3.

Example 9

Synthesis ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl (3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)am ino)-3- oxopropyl)carbamate

The title compound was prepared by proceeding analogously as described in Example 8, Steps 1- 3, using 3-(tert-butoxycarbonylamino)propanoic acid instead of 3-[tert-butoxycarbonyl(methyl)- amino]propanoic acid in Step 1. MS (ES, m/z): [M+H] ⁺ = 995.3.

Example 10

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl (2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)ethyl)(methyl)carbamate The title compound was prepared by proceeding analogously as described in Example 1 , Steps 11 and 12, using 2-(2,6-dioxopiperidin-3-yl)-4-((2-(methylamino)ethyl)amino)i soindoline-l, 3-dione (ref: WO2022/147465) instead of 4-((2-(2-(2-aminoethoxy)ethoxy)-ethyl)amino)-2-(2,6-dioxopip eridin-3- yl)isoindoline- 1,3-dione in Step 11. MS (ES, m/z): [M+H] ⁺ = 981.3.

Example 11

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl (2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-

The title compound was prepared by proceeding analogously as described in Example 1 , Steps 11 and 12, using 4-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl) isoindoline- 1,3-dione (ref: WO2022/147465A1) instead of 4-((2-(2-(2-aminoethoxy)ethoxy)-ethyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-l, 3-dione in Step 11. MS (ES, m/z): [M+H] ⁺ = 967.3.

Example 12

Synthesis of ((3S,7aS)-7a-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-e thynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl (2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)- amino)ethyl)(methyl) carbamate

The title compound was prepared by proceeding analogously as described in Example 1 , Steps 11 and 12, using 2-(2,6-dioxopiperidin-3-yl)-5-((2-(methylamino)ethyl)amino)i soindoline-l, 3-dione (ref: WO2022/99117) instead of 4-((2-(2-(2-aminoethoxy)ethoxy)-ethyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-l, 3-dione in Step 11. MS (ES, m/z): [M+H] ⁺ = 981.3.

Example 13

Synthesis of ((3R,7aR)-7a-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-e thynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl (2-(2-(2-(3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindoli n-4-yl)amino)- 3-oxopropoxy)ethoxy)ethoxy)ethyl)carbamate

The title compound was prepared by proceeding analogously as described in Example 1 , Steps 11 and 12, using 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)-N-(2-(2,6-dioxo piperidin-3-yl)-l,3- dioxoisoindolin-4-yl)propanamide (ref: J. Med. Chem. 2019, 62, 2508 - 2520) instead of 4-((2-(2-(2- aminoethoxy)ethoxy)-ethyl)amino)-2-(2,6-dioxopiperidin-3-yl) isoindoline- 1,3-dione in Step 11. MS (ES, m/z): [M+H] ⁺ = 1127.3.

Example 14

Synthesis of ((3S,7aS)-7a-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-e thynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl (6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)hexyl)carbamate

The title compound was prepared by proceeding analogously as described in Example 1 , Steps 11 and 12, using 5-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoli ne-l, 3-dione (ref: WO2020/38415) instead of 4-((2-(2-(2-aminoethoxy) ethoxy)-ethyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline- 1,3-dione in Step 11. MS (ES, m/z): [M+H] ⁺ = 1023.3. Example 15

Synthesis of ((3S,7aS)-7a-(((4-((lR,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-

1 H-pyrrolizin-3 -yl)methyl ( 1 -((3 -(3 -(4-(3 -(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)- 1 -methyl- 1 H- indazol-6-yl)piperidin-l-yl)-2-methylpropyl)phenyl)sulfonyl) piperidin-4-yl)carbamate

Step 1: tert-butyl (l-((3-(2-methyl-3-oxopropyl)phenyl)sulfonyl)piperidin-4-yl) carbamate

A mixture of palladium(II) acetate (53.54 mg, 0.24 mmol) and tetrabutylammonium bromide (4000 mg, 12.41 mmol) was heated to 130 °C under argon atmosphere, then tert-butyl (l-((3- bromophenyl)sulfonyl)piperidin-4-yl)carbamate (1.0 g, 2.38mmol), 2-methylprop-2-en-l-ol (515.89 mg, 7.15 mmol) and sodium bicarbonate (400.69 mg, 4.77 mmol) were added. The resulting mixture was stirred at 130 °C for 4 h. After cooling to rt, water and EtOAc were added, and the mixture was filtered. The phases were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure, The residue was purified by silica gel chromatography, eluted with EtOAc/petroleum ester (0—21% with 5% dichloromethane) to afford the title compound (830 mg).

Step 2 : tert-butyl ( 1 -((3 -(3 -(4-(3 -(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)- 1 -methyl- 1 H-indazol-6- yl)piperidin-l-yl)-2-methylpropyl)phenyl)sulfonyl)piperidin- 4-yl)carbamate

A mixture of tert-butyl (l-((3-(2-methyl-3-oxopropyl)phenyl)sulfonyl)piperidin-4- yl)carbamate hydrochloride (100 mg, 0.24 mmol) and l-(l-methyl-6-(piperidin-4-yl)-lH-indazol-3- yl)dihydropyrimidine-2,4(lH,3H)-dione hydrochloride (88.63 mg, 0.24 mmol) in anhydrous dichloromethane (2 mL) was stirred at 25 °C for 3 h. Sodium triacetoxyborohydride (154.88 mg, 0.73 mmol) was added and the resulting mixture was stirred for another 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluted with methanol/dichloromethane (0~5%) to afford the title compound (62 mg).

Step 3: ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl (1 -((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l -methyl- 1H- indazol-6-yl)piperidin-l-yl)-2-methylpropyl)phenyl)sulfonyl) piperidin-4-yl)carbamate

The title compound was prepared by proceeding analogously as described in Example 8, Steps 2 and 3, using tert-butyl (l-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-me thyl-lH- indazol-6-yl)piperidin- 1 -yl)-2-methylpropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate instead of tertbutyl N-[3-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]a mino]-3-oxo-propyl]-N- methylcarbamate in Step 2. MS (ES, m/z): [M+H] ⁺ = 1272.6.

Example 16

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl (5-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)am ino)-5-

The title compound was prepared by proceeding analogously as described in Example 8, Steps 1-3, using 5-(tert-butoxycarbonylamino)pentanoic acid instead of 3-[tert-butoxycarbonyl(methyl)- amino]propanoic acid in Step 1. MS (ES, m/z): [M+H] ⁺ = 1023.3.

Example 17

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl (5-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)am ino)-5-

The title compound was prepared by proceeding analogously as described in Example 1 , Steps 11 and 12, using 5-amino-N-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4 -yl)pentanamide hydrochloride (ref: CN114853735,2022, A) instead of 4-((2-(2-(2-aminoethoxy)ethoxy)- ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione in Step 11. MS (ES, m/z): [M+H] ⁺ = 1023.4

Example 18

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl (7-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)hep t-6-yn-l- yl)carbamate

The title compound was prepared by proceeding analogously as described in Example 1 , Steps 11 and 12, using 4-(7-aminohept-l-yn-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindo line-l, 3-dione hydrochloride (ref: WO2021/201577) instead of 4-((2-(2-(2-aminoethoxy)ethoxy)-ethyl)amino)-2- (2, 6-dioxopiperidin-3-yl)isoindoline-l, 3-dione in Step 11. MS (ES, m/z): [M+H] ⁺ = 1018.4.

Example 19

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl (7-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)hep tyl)carbamate

Step 1: tert-butyl (7-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)hep tyl)carbamate

To a solution of tert-butyl N-[7-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]he pt-6- ynyl] carbamate (50 mg, 0.11 mmol) in ethanol (0.5 mL) and THF (0.5 mL) was added Pd/C (10 mg) and the resulting mixture was stirred for 40 h under H2 atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford the title compound (50 mg).

Step 2. ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl (7-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)hep tyl)carbamate

The title compound was prepared by proceeding analogously as described in Example 8, Steps 2 and 3, using tert-butyl (7-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)hep tyl)carbamate instead of tert-butyl (3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)am ino)-3- oxopropyl)(methyl)carbamate in Step 2. MS (ES, m/z): [M+H] ⁺ = 1022.4.

Example 20

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl (7-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)hep tyl)carbamate

Step 1 : tert-butyl (7-(2-(2,6-dioxopiperidin-3-yl)-l ,3-dioxoisoindolin-5-yl)hept-6-yn-l-yl)carbamate

A mixture of 5-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-l, 3-dione (100 mg, 0.3 mmol), tert-butyl N-hept-6-ynylcarbamate (94.01 mg, 0.44 mmol), Pd(pph3)2C12 (20.82 mg, 0.03 mmol), Cui (11.3 mg, 0.06 mmol) and triethylamine (1.0 mL, 7.17 mmol) in anhydrous DMF (2 mL) was stirred at 70 °C for 3 h. After cooling to rt, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluted with methanol/dichloromethane (0~4%) to afford the title compound (100 mg).

Step 2: tert-butyl (7-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)hep tyl)carbamate BocHN

To a mixture of tert-butyl N-[7-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]he pt-6- ynyl] carbamate (50 mg, 0.11 mmol) in ethanol (1 mL) was added Pd/C (10 mg) and the resulting mixture was stirred for 18 h under H2 atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure to afford the title compound (50 mg).

Step 3: ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl (7-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)hep tyl)carbamate

The title compound was prepared by proceeding analogously as described in Example 8, Steps 2 and 3, using tert-butyl (7-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)hep tyl) carbamate instead of tert-butyl (3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)am ino)-3- oxopropyl)(methyl)carbamate in Step 2. MS (ES, m/z): [M+H] ⁺ = 1022.3.

Example 21

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro-

1 H-pyrrolizin-3 -yl)methyl 4-(3 -(2 ,4-dioxotetrahydropyrimidin- 1 (2H)-yl)- 1 -methyl- 1 H-indazol-6-yl)- The title compound was prepared by proceeding analogously as described in Example 1 , Steps 11 and 12, using l-(l-methyl-6-(piperidin-4-yl)-lH-indazol-3-yl)dihydropyrimi dine-2,4(lH,3H)- dione hydrochloride (ref: WO2021/127561) instead of 4-((2-(2-(2-aminoethoxy)ethoxy)- ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione in Step 11. MS (ES, m/z): [M+H] ⁺ = 979.3.

Example 22

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl (3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)- amino)propyl)(methyl)carbamate

The title compound was prepared by proceeding analogously as described in Example 1 , Steps 11 and 12, using 2-(2,6-dioxopiperidin-3-yl)-4-((3-(methylamino)propyl)amino) isoindoline-l, 3-dione (ref: WO2022/147465) instead of 4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-l, 3-dione in Step 11. MS (ES, m/z): [M+H] ⁺ = 995.3.

Example 23

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl (3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl) amino)propyl) carbamate The title compound was prepared by proceeding analogously as described in Example 1 , Steps 11 and 12, using 4-((3-aminopropyl)amino)-2-(2,6-dioxopiperidin-3-yl) isoindoline- 1,3-dione (ref: J. Med. Chem, 2019, 62, 448 - 466) instead of 4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-l, 3-dione in Step 11. MS (ES, m/z): [M+H] ⁺ = 981.3.

Example 24

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro-

1 H-pyrrolizin-3 -yl)methyl 4-(4-(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)phenyl)piperazine- 1 - carboxylate

The title compound was prepared by proceeding analogously as described in Example 1 , Steps 11 and 12, using l-(4-(piperazin-l-yl)phenyl)dihydropyrimidine-2,4(lH,3H)-dio ne (ref: WO2022/147465) instead of 4-((2-(2-(2-aminoethoxy)ethoxy)-ethyl)amino)-2-(2,6-dioxopip eridin-3- yl)isoindoline- 1,3-dione in Step 11. MS (ES, m/z): [M+H] ⁺ = 926.3

Example 25

Synthesis of ((3S,7aS)-7a-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-e thynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl 4-(3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)propyl)piperidine- 1 -carboxylate Step 1: tert-butyl 4-(3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl) amino)propyl)- piperidine- 1 -carboxylate

A mixture of 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-l, 3-dione (138 mg, 0.5 mmol), tertbutyl 4-(3-aminopropyl)piperidine-l -carboxylate (121 mg, 0.5 mmol) and N,N-diisopropyl ethylamine (194 mg, 1.5 mmol) in 1 mL of DMF was stirred at 105 °C for 12 h. After cooling to rt, the reaction mixture was diluted with water and precipitates were isolated by filtration. The precipitates was dissolved in DCM, dried over Na2SO4 and concentrated in vacuum. The residue was purified by column chromatography, eluted with EtOAc/PE = 0-50% to afford the title compound (130 mg). Step 2: ((3S,7aS)-7a-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-e thynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl 4-(3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)propyl)piperidine- 1 -carboxylate

The title compound was prepared by proceeding analogously as described in Example 8, Steps 2 and 3, using tert-butyl 4-(3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl) amino)- propyl)piperidine-l -carboxylate instead of tert-butyl (3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo- isoindolin-5-yl)amino)-3-oxopropyl)(methyl)carbamate in Step 2. MS (ES, m/z): [M+H] ⁺ = 1049.3.

Example 26

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl 4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l -methyl- lH-indazol-6- yl)piperazine- 1 -carboxylate

The title compound was prepared by proceeding analogously as described in Example 1 , Steps 11 and 12, using l-(l-methyl-6-(piperazin-l-yl)-lH-indazol-3-yl)dihydropyrimi dine-2,4(lH,3H)- dione (ref: WO2021/127561) instead of 4-((2-(2-(2-aminoethoxy)ethoxy)-ethyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-l, 3-dione in Step 11. MS (ES, m/z): [M+H] ⁺ = 980.4.

Example 27

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)o xy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl 4-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)ethyl)piperazine- 1 -carboxylate

The title compound was prepared by proceeding analogously as described in Example 1 , Steps 11 and 12, using 2-(2,6-dioxopiperidin-3-yl)-4-((2-(piperazin-l-yl)ethyl)amin o)isoindoline- 1,3-dione (ref: J. Med. Chem, 2021, 64, 1626 - 1648) instead of 4-((2-(2-(2-aminoethoxy)ethoxy)-ethyl)amino)- 2-(2,6-dioxopiperidin-3-yl) isoindoline- 1,3-dione in Step 11. MS (ES, m/z): [M+H] ⁺ = 1020.4.

Example 28

Synthesis of ((3S,7aS)-7a-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-e thynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl 4-(3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl) - amino)propyl)piperidine- 1 -carboxylate

The title compound was prepared by proceeding analogously as described in Example 1 , Steps 11 and 12, using 2-(2,6-dioxopiperidin-3-yl)-4-((3-(piperidin-4-yl)propyl) amino)isoindoline- 1,3- dione (ref: J. Med. Chem, 2021, 64, 1626 - 1648) instead of 4-((2-(2-(2-aminoethoxy)ethoxy)- ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione in Step 11. MS (ES, m/z): [M+H] ⁺ = 1049.3.

Example 29

Synthesis of ((3S,7aS)-7a-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-e thynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl 3-(((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)methyl)pyrrolidine- 1 -carboxylate

The title compound was prepared by proceeding analogously as described in Example 1 , Steps 11 and 12, using 2-(2,6-dioxopiperidin-3-yl)-4-((pyrrolidin-3-ylmethyl)amino) isoindoline-l, 3-dione (ref: W02017/197051) instead of 4-((2-(2-(2-aminoethoxy)ethoxy)-ethyl)amino)-2-(2,6- dioxopiperidin-3-yl)isoindoline-l, 3-dione in Step 11. MS (ES, m/z): [M+H] ⁺ = 1007.3.

Example 30

Synthesis of ((3S,7aS)-7a-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-e thynyl-7-fluoro-3- hydroxynaphthalen- 1 -yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy) methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl 3-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl) - amino)ethyl)azetidine- 1 -carboxylate

The title compound was prepared by proceeding analogously as described in Example 1 , Steps 11 and 12, using 4-((2-(azetidin-3-yl)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl )isoindoline-l, 3-dione, (ref: W02021/127190) instead of 4-((2-(2-(2-aminoethoxy)ethoxy)-ethyl)amino)-2-(2,6-dioxo- piperidin-3-yl)isoindoline-l,3-dione in Step 11. MS (ES, m/z): [M+H] ⁺ = 1007.3.

Example 31

Synthesis of ((3S,7aS)-7a-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-e thynyl-7-fluoro-3- hydroxynaphthalen- 1 -yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-6-methy l enehexahydro- lH-pyrrolizin-3-yl)methyl 3-(((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)methyl)pyrrolidine- 1 -carboxylate

Step 1: tert-butyl 3-(((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)am ino)methyl)- pyrrolidine- 1 -carboxylate

A solution of 2-(2,6-dioxo-3-piperidyl)-5-fluoroisoindoline-l, 3-dione (138 mg, 0.5 mmol), tert-butyl 3-(aminomethyl)pyrrolidine-l -carboxylate (100 mg, 0.5 mmol), N,N-diisopropyl ethylamine (194 mg, 1.5 mmol) in 1 mL of DMF was stirred at 105 °C for 12 h. After cooling to rt, the reaction mixture was diluted with water, extracted by DCM, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with EtOAc/PE = 0-60% to afford the title compound (100 mg).

Step 2: ((3S,7aS)-7a-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-e thynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methyl enehexahydro- lH-pyrrolizin-3-yl)methyl 3-(((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)am ino)- methyl)pyrrolidine- 1 -carboxylate

The title compound was prepared by proceeding analogously as described in Example 8, Steps 2 and 3, using tert-butyl 3-(((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)am ino)methyl)- pyrro li dine- 1 -carboxylate instead of tert-butyl (3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)-3-oxopropyl)(methyl)carbamate in Step 2. MS (ES, m/z): [M+H] ⁺ = 1007.3.

Example 32

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl 4-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl) amino)-2- oxoethyl)piperidine- 1 -carboxylate

Step 1 : tert-butyl 4-(2-((2-(2,6-dioxopiperidin-3-yl)-l ,3-dioxoisoindolin-4-yl)amino)-2-oxoethyl)- piperidine- 1 -carboxylate

To a solution of 4-amino-2-(2,6-dioxo-3-piperidyl)isoindoline- 1,3 -dione (200 mg, 0.73 mmol) and 2-( 1 -tert-butoxycarbonyl-4-piperidyl)acetic acid (213.69 mg, 0.88 mmol) in anhydrous DMF (3 ml) was added N,N-dimethylpyridin-2-amine (268.26 mg, 2.2 mmol), followed by l-chloro-N,N,2- trimethylprop- 1 -en- 1 -amine (195.6 mg, 1.46 mmol) and the resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by Prep-HPLC (0-70% acetonitrile in water with 0.05% formic acid) to afford the title compound (100 mg).

Step 2: ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl 4-(2-((2-(2,6-dioxopiperi din-3 -yl)- 1,3 -di oxoisoindolin-4-yl)amino)-2- oxoethyl)piperidine- 1 -carboxylate

The title compound was prepared by proceeding analogously as described in Example 8, Steps 2 and 3, using tert-butyl 4-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl) amino)-2- oxoethyl)piperidine-l -carboxylate instead of tert-butyl (3-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)amino)-3-oxopropyl)(methyl)carbamate in Step 2. MS (ES, m/z): [M+H] ⁺ = 1049.4

Example 33

Synthesis of ((3S,7aS)-7a-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-e thynyl-7-fluoro-3- hydroxynaphthalen- 1 -yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy) methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl 2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)carbamoyl)morpholine-4-carboxylate

The title compound was prepared by proceeding analogously as described in Example 32, Steps 1 and 2, using 4-tert-butoxycarbonylmorpholine-2-carboxylic acid instead of 2-(l-tert- butoxycarbonyl-4-piperidyl)acetic acid in Step 1. MS (ES, m/z): [M+H] ⁺ = 1023.3.

Example 34

Synthesis of ((3S,7aS)-7a-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-e thynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl (4-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)oxy)bu tyl)carbamate

The title compound was prepared by proceeding analogously as described in Example 1 , Steps 11 and 12, using 3 -(4-(4-aminobutoxy)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (ref: WO2022/148459) instead of 4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopipe ri din-3 - yl)isoindoline- 1,3-dione in Step 11. MS (ES, m/z): [M+H] ⁺ = 982.3.

Example 35

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro-

1 H-pyrrolizin-3 -yl)methyl 4-(2-(2 ,6-dioxopiperidin-3 -yl)- 1 -oxoisoindolin-5-yl)piperidine- 1 - carboxylate

The title compound was prepared by proceeding analogously as described in Example 1 , Steps 11 and 12, using 3-(l-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2, 6-dione (ref: WO2021/87093) instead of 4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopipe ridin-3- yl)isoindoline- 1,3-dione in Step 11. MS (ES, m/z): [M+H] ⁺ = 978.4.

Example 36

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro-

1 H-pyrrolizin-3 -yl)methyl 4-(2-(2 ,6-dioxopiperidin-3 -yl)- 1 -oxoisoindolin-4-yl)piperidine- 1 - carboxylate

The title compound was prepared by proceeding analogously as described in Example 1 , Steps 11 and 12, using 3-(l-oxo-4-(piperidin-4-yl)isoindolin-2-yl)piperidine-2, 6-dione (ref: WO2017/197056) instead of 4-((2-(2-(2-aminoethoxy) ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3- yl)isoindoline- 1,3-dione in Step 11. MS (ES, m/z): [M+H] ⁺ = 978.4.

Example 37

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro-

1 H-pyrrolizin-3 -yl)methyl 4-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl) amino)-2- oxoethyl)piperidine- 1 -carboxylate

The title compound was prepared by proceeding analogously as described in Example 8, Steps 1-3, using 2-(l-tert-butoxycarbonyl-4-piperidyl)acetic acid instead of 3-[tert-butoxycarbonyl(methyl)- amino]propanoic acid in Step 1. MS (ES, m/z): [M+H] ⁺ = 1049.4.

Example 38

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl(4-((2-(2,6-dioxopiperidin-3-yl)-l -oxoisoindo lin-5-yl)oxy)butyl)carbamate

Step 1: tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)oxy)bu tyl)carbamate

A mixture of 3-(5-hydroxy-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (260 mg, 1 mmol), tertbutyl (4-bromobutyl)carbamate (252 mg, 1 mmol) and K2CO3 (207 mg, 1.5 mmol) in ACN (2 mL) was stirred at 85 °C for 12 h under argon atmosphere. After cooling to rt, the reaction mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with MeOH/DCM = 0-8% to yield the title compound (80 mg).

Step 2: ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl(4-((2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-5-yl)oxy)butyl)carbamate

The title compound was prepared by proceeding analogously as described in Example 8, Steps 2 and 3, using tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)oxy)bu tyl)carbamate instead of tert-butyl (3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)am ino)-3- oxopropyl)(methyl)carbamate in Step 2. MS (ES, m/z): [M+H] ⁺ = 982.4.

Example 39

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl(2-((2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-5-yl)oxy)ethyl)carbamate

Step 1: tert-butyl (2-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)oxy)et hyl)carbamate

A mixture of 3-(5-hydroxy-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (65 mg, 0.25 mmol), tert-butyl (2-bromoethyl)carbamate (63 mg, 0.25 mmol) and K2CO3 (52 mg, 0.37 mmol) in ACN (2 mL) was stirred at 85 °C for 12 h under argon atmosphere. The reaction mixture was filtered, and the filtrate was concentrated in vacuum. The residue was purified by silica gel chromatography, eluted with MeOH/DCM = 0-8% to afford the title compound (60 mg).

Step 2: ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl(2-((2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-5-yl)oxy)ethyl)carbamate

The title compound was prepared by proceeding analogously as described in Example 8, Steps 2 and 3, using tert-butyl (2-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)oxy)et hyl)carbamate instead of tert-butyl (3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)am ino)-3- oxopropyl)(methyl)carbamate in Step 2. MS (ES, m/z): [M+H] ⁺ = 954.3.

Example 40

Synthesis of ((3S,7aS)-7a-(((4-((lR,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-

1 H-pyrrolizin-3 -yl)methyl( 1 -((4-((4-(3-(2,4-dioxo tetrahydropyrimidin- 1 (2H)-yl)- 1 -methyl- 1 H- indazol-6-yl)piperidin- 1 -yl)methyl) phenyl)sulfonyl)piperidin-4-yl)carbamate

The title compound was prepared by proceeding analogously as described in Example 1 , Steps 11 and 12, using l-(6-(l-(3-((4-aminopiperidin-l-yl)sulfonyl)benzyl) piperidin-4-yl)- 1 -methyl- 1 H- indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione instead of 4-((2-(2-(2- aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)i soindoline- 1,3-dione in Step 11. MS (ES, m/z): [M+H] ⁺ = 1230.5.

Example 41

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen- l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-6-meth ylenehexahydro- lH-pyrrolizin-3-yl)methyl 4-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)ethyl)piperidine- 1 -carboxylate

Step 1: tert-butyl 4-(2-(tosyloxy)ethyl)piperidine-l -carboxylate

To a solution of tert-butyl 4-(2 -hydroxyethyl)piperi dine- 1 -carboxylate (500 mg, 2.18 mmol) and

4-methylbenzenesulfonyl chloride (623.5 mg, 3.27 mmol) in anhydrous DCM (10 mL) was added 4- dimethylaminopyridine (266.37 mg, 2.18 mmol) at rt and the resulting mixture was stirred at this temperature for 18 h. The reaction mixture was quenched with 1.0 M hydrogen chloride aq. solution and then extracted with EtOAc. The combined organic layers were washed with 10% sodium hydroxide, water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluted with EtOAc/petroleum (0~20%) to afford the title compound (490 mg).

Step 2: tert-butyl 4-(2-((2-(2,6-dioxopiperi din-3 -yl)- 1,3 -di oxoisoindolin-4-yl)oxy) ethyl)piperidine-l- carboxylate

To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-l, 3-dione (178.77 mg, 0.65 mmol) and tert-butyl 4-(2-(tosyloxy)ethyl)piperi dine- 1 -carboxylate (250 mg, 0.65 mmol) in anhydrous DMF (3 mL) was added sodium carbonate (138.19 mg, 1.3 mmol) and the resulting mixture was stirred at 80 °C for 16 h under argon atmosphere. After cooling to rt, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and concentrated. The residue was purified by silica gel chromatography, eluted with methanol/di chloromethane (0~3%) to afford the title compound (250 mg).

Step 3: ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl 4-(2-((2-(2,6-dioxopiperi din-3 -yl)- 1,3 -di oxoisoindolin-4-yl)oxy)- ethyl)piperidine- 1 -carboxylate

The title compound was prepared by proceeding analogously as described in Example 8, Steps 2 and 3, using tert-butyl 4-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl) oxy) ethyl)piperidine-l -carboxylate instead of tert-butyl (3-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)amino)-3-oxopropyl)(methyl)carbamate in Step 2. MS (ES, m/z): [M+H] ⁺ = 1036.4.

Example 42

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl 4-(2-((2-(2,6-dioxo piperidin-3-yl)-l ,3-dioxoisoindolin-5- yl)oxy)ethyl)piperidine- 1 -carboxylate

The title compound was prepared by proceeding analogously as described in Example 41, Steps 2-3, using 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-l, 3-dione instead of 2-(2,6- dioxopiperidin-3-yl)-4-hydroxyisoindoline-l, 3-dione in step 2. MS (ES, m/z): [M+H] ⁺ = 1036.5. Example 43

Synthesis of ((3S,7aS)-7a-(((4-((lR,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- lH-pyrrolizin-3-yl)methyl 2-(((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)methyl)morpholine-4-carboxylate

Step 1: tert-butyl 2-(((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)ox y) methyl)morpholine- 4-carboxylate

To a solution of tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (109 mg, 0.5 mmol), 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline- 1,3-dione (165 mg, 0.6 mmol) and PPI13 (158 mg, 0.6 mmol) in anhydrous THF (2 mL), was added DIAD (122 mg, 0.6 mmol) dropwise at 0 °C. The resulting mixture was stirred for 12 h at rt. The reaction mixture was quenched by water, extracted by DCM, dried over Na2SO4, and concentrated in vacuum. The residue was purified by flash, eluted with MeOH/DCM = 0-6% to yield the title compound (60 mg, 25%) as a yellow oil.

Step 2: ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy) methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl 2-(((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)methyl)morpholine-4-carboxylate

The title compound was prepared by proceeding analogously as described in Example 8, Steps 2 and 3, using tert-butyl 2-(((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)ox y) methyl)morpholine-4-carboxylate instead of tert-butyl (3-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)amino)-3-oxopropyl)(methyl)carbamate in Step 2. MS (ES, m/z): [M+H] ⁺ = 1024.3.

Example 44

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl 4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)ethynyl )piperidine-l- carboxylate

Step 1: tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-3 -oxoisoindo lin-4-yl)ethynyl)piperi dine- 1- carboxylate

A mixture of 3-(7-bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (323 mg, 1 mmol), tertbutyl 4-ethynylpiperidine-l -carboxylate (418 mg, 2 mmol), Cui (38 mg, 0.2 mmol), Pd(PPh3)3C12 (70.1 mg, 0.1 mmol) and TEA (1 mL) in DMF (2 mL) was stirred at 85 °C for 3 h under argon atmosphere. After cooling to rt, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuum. The residue was purified by flash, eluted with MeOH/DCM = 0-6% to yield the title compound (260 mg). Step 2: ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8- ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoropyrido[4, 3-d]pyrimidin-2-yl)oxy)methyl)-6- methylenehexahydro-lH-pyrrolizin-3-yl)methyl 4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4- yl)ethynyl)piperidine- 1 -carboxylate

The title compound was prepared by proceeding analogously as described in Example 8, Steps 2 and 3, using tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)ethynyl )piperidine-l- carboxylate instead of tert-butyl (3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)am ino)-3- oxopropyl)(methyl)carbamate in Step 2. MS (ES, m/z): [M+H] ⁺ = 1002.4.

Example 45

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl 4-(4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)carb amoyl)-lH- 1 ,2,3-triazol- 1 -yl) piperidine- 1 -carboxylate

The title compound was prepared by proceeding analogously as described in Example 32, Steps 1 and 2, using l-(l-(tert-butoxycarbonyl)piperidin-4-yl)-lH-l,2,3-triazole- 4-carboxylic acid instead of 2-(l-tert-butoxycarbonyl-4-piperidyl)acetic acid and 3-(7-amino-l-oxoisoindolin-2- yl)piperidine-2, 6-dione instead of 4-amino-2-(2,6-dioxo-3-piperidyl)isoindoline-l,3-dione in Step 1. MS (ES, m/z): [M+H] ⁺ = 1088.3. Example 46

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl 4-(2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)ethyl )piperidine-l-

Step 1: tert-butyl 4-(2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)ethyl )piperidine-l- carboxylate

To a solution of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)ethynyl )- piperidine- 1 -carboxylate (200 mg, 0.44 mmol) in EtOAc (2 mL) was added ammonium formate (140 mg, 2.2 mmol) and Pd/C (40 mg). The reaction was stirred for 3 h at 25 °C under hydrogen atmosphere. The reaction mixture was diluted with EtOAc and filtered. The filtrate was washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with MeOH/DCM = 0-6%, to afford the title compound (160 mg). Step 2: ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl 4-(2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)ethyl )piperidine-l- carboxylate The title compound was prepared by proceeding analogously as described in Example 8, Steps 2 and 3, using tert-butyl 4-(2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)ethyl )piperidine-l- carboxylate instead of tert-butyl (3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)am ino)-3- oxopropyl)(methyl)carbamate in Step 2 MS (ES, m/z): [M+H] ⁺ = 1006.3.

Example 47

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)o xy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl 4-((l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl) piperidin-4- yl)oxy)piperidine- 1 -carboxylate

Step 1 : tert-butyl 4- [ [ 1 - [2-(2,6-dioxo-3 -piperidyl)- 1 ,3 -dioxo-isoindolin-5-yl] -4-piperidyl] oxy] - piperidine- 1 -carboxylate

To a solution of tert-butyl 4-(4-piperidyloxy)piperidine- 1 -carboxylate (340 mg, 1.19 mmol, 1.1 eq) and 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline- 1,3-dione (300 mg, 1.09 mmol, 1.0 eq) in anhydrous NMP (10 mL), was added N,N-diisopropyl ethylamine (0.28 mL, 1.63 mmol, 1.5 eq) and the resulting mixture was stirred at 130 °C for 3 h. After cooling to rt, the reaction mixture was diluted with water, then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH/DCM (0-3%) to afford the title compound (400 mg).

Step 2: 2-(2,6-dioxo-3-piperidyl)-5-[4-(4-piperidyloxy)-l-piperidyl] isoindoline- 1,3-dione hydrochloride salt To a solution of tert-butyl 4-[[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]- 4- piperidyl]oxy]piperidine-l -carboxylate (400 mg, 0.74 mmol, 1.0 eq) in anhydrous DCM (20 mL) at 25 °C was added HC1 solution in 1,4-dioxane (4.0 M, 3.7 mL, 14.8 mmol, 20.0 eq) and the resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was recrystallized from EtOAc to afford the title compound as HC1 salt (300 mg). Step 3: 8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthale n-l-yl)pyrido[4,3-d]-pyrimidine-

2,4-diol

To a solution 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-l,3,2-dioxaborolan-2-yl)na phthalen-l-yl)ethynyl)- triisopropylsilane (10.9 g, 24.1 mmol, 1.3 eq.) in EtOH (150 mL) and H2O (50 mL) was 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 °C under nitrogen atmosphere. After cooling to rt, the reaction mixture was diluted with water, extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4 and 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 4: 7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]p yrimidine-2,4-diol

A mixture of 8-fluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthale n-l-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 °C 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 5: 2,4-dichloro-7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluorop yrido[4,3-d]pyrimidine

To a solution of POCh (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-l-yl)-8-fluoropyrido[4,3-d]- pyrimidine-2,4-diol (1.2 g, 3.4 mmol, 1.0 eq.) in portions at 0-5 °C and the resulting mixture was stirred at 50 °C for 1 h. After cooling to rt, the reaction 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 and concentrated to afford the title compound (1.5 g).

Step 6: tert-butyl (lR,5S)-3-(2-chloro-7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8- fluoropyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylat e

To a solution of 2,4-dichloro-7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluorop yrido-[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 °C and the resulting solution was stirred at -40 °C for 5 mins. A solution of tertbutyl (lR,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (870 mg, 4.1 mmol, 1.1 eq.) in THF (5 mL) was added to the above reaction mixture dropwise and the resulting mixture was stirred for additional 15 mins at -40 °C. 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 7: tert-butyl (lR,5S)-3-(2-(((5S,7aS)-5-(((tert-butyldiphenylsilyl)oxy)met hyl)-2-methylene- tetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethynyl-7-f luoro naphthalen-l-yl)-8- fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oc tane-8-carboxylate To a solution of ((5R,7aR)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-methyle netetrahydro- lH-pyrrolizin-7a(5H)-yl)methanol (1 -.65 g, 3.9 mmol, 1.1 eq) in THF (20 mL) was added NaH (427 mg, 10.7 mmol, 60% purity) at 0 °C and the resulting mixture was stirred at 0 °C for 30 min. Tertbutyl (lR,5S)-3-(2-chloro-7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8- fluoropyrido[4,3-d]pyrimidin-4- yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.0 g, 3.6 mmol, 1.0 eq) was added to the above mixture at 0 °C and the the mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched by NH4CI (sat aq.) at 0 °C, and then extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with MeOH/DCM (0-5%), to give the title compound (3.0 g).

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

To a solution of tert-butyl (lR,5S)-3-(2-(((5S,7aS)-5-(((tert-butyldiphenylsilyl) oxy)methyl)- 2 -methylenetetrahydro- 1 H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphtha len- 1 -yl)-8- fluoropyrido[4,3-d] pyramidin-4-yl)-3,8-diazabicyclo [3.2.1]octane-8-carboxylate (3.0 g, 3.2 mmol, 1.0 eq) in THF (10 mL) was added TBAF THF solution (1.0 M, 12.7 mL, 4.0 eq) and the resulting mixture was stirred at 25 °C for 2 hours. The mixture was then concentrated, and the residue was purified by silica gel column chromatography, eluted with MeOH/DCM (0-5%) to give the title compound (2.0 g).

Step 9: tert-butyl (lR,5S)-3-(7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2- (((5S,7aS)-2- methylene-5-((((4-nitrophenoxy)carbonyl)oxy)methyl)tetrahydr o-lH-pyrrolizin-7a(5H)- yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2 .1] octane-8-carboxylate To a solution of TEA (0.31 mL, 2.26 mmol) and tert-butyl (lR,5S)-3-(7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoro-2-(((5S,7aS)-5-(hydroxymethy l)-2-methylene tetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3, 8-diazabicyclo[3.2.1]octane-8- carboxylate (200 mg, 0.28 mmol) in anhydrous THF (1 mL) was added (4-nitrophenyl) carbonochloridate (199 mg, 0.99 mmol) at 25 °C and the resulting mixture was stirred at 25 °C for 16 h under Ar atmosphere. The reaction mixture was diluted with water, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-50%) to afford the title compound (130 mg).

Step 10: tert-butyl (lR,5S)-3-(2-(((5S,7aS)-5-(((4-((l-(2-(2,6-dioxopiperidin-3- yl)-l,3-dioxo- isoindolin-5-yl)piperidin-4-yl)oxy)piperidine-l-carbonyl)oxy )methyl)-2-methylenetetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthale n-l-yl)-8-fluoropyrido[4,3-d]- pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] octane-8-carboxylate

To a solution of 2-(2,6-dioxo-3-piperidyl)-5-[4-(4-piperidyloxy)-l-piperidyl] isoindoline-l,3- dione (HC1 salt, 142 mg, 0.3 mmol), TEA (151 mg, 1.49 mmol) in anhydrous THF (4.5 mL) and NMP (1.5 mL) was added tert-butyl (lR,5S)-3-(7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2- (((5S,7aS)-2-methylene-5-((((4-nitrophenoxy)carbonyl)oxy)met hyl)tetrahydro-lH-pyrrolizin-7a (5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicycl o[3.2.1]octane-8-carboxylate (130 mg, 0.1488 mmol) at 25 °C and the resulting mixture was stirred at 25 °C for 16 h. To the reaction mixture was added water and saturated NaHC'CF, at 25 °C. The resulting mixture was stirred at 25 °C for 10 min. The mixture was extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with MeOH/DCM (0-5%) to afford the title compound (122 mg).

Step 11: ((3S,7aS)-7a-(((4-((lR,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-methy lenehexahydro- 1 H- pyrrolizin-3-yl)methyl 4-((l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl) piperidin-4-yl)- oxy)piperidine- 1 -carboxylate

To a solution of tert-butyl (lR,5S)-3-(2-(((5S,7aS)-5-(((4-((l-(2-(2,6-dioxopiperidin-3- yl)-l,3- dioxoisoindolin-5-yl)piperidin-4-yl)oxy)piperidine-l-carbony l)oxy)methyl)-2-methylenetetrahydro- lH-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphth alen-l-yl)-8-fluoropyrido[4,3-d]- pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (122 mg, 0.1038 mmol) in anhydrous DCM (10 mL) at -10 °C was added HCl/l,4-di oxane (0.52 mL, 2.08 mmol) dropwise and the resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was then concentrated under reduced pressure. The residue was diluted with DCM (10 mL) and basified with NHs/MeOH (0.5 mL) at -78 °C. The resulting mixture was concentrated under reduced pressure and the residue was purified by Cl 8 column chromatography, eluted with MeCN/water (0-60%, 0.05% NH4HCO3) to afford the title compound (70.5 mg). MS (ES, m/z): [M+H] ⁺ = 1075.4.

Example 48

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)o xy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl 4-(l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)p iperidine-4- carbonyl)piperazine- 1 -carboxylate Step 1: tert-butyl 4-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]pi peridine-4- carbonyl]piperazine- 1 -carboxylate

To a solution of tert-butyl 4-(piperidine-4-carbonyl)piperazine- 1 -carboxylate (592 mg, 1.99 mmol) and 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-l,3-dione (500 mg, 1.81 mmol) in anhydrous NMP (10 mL) was added N,N-diisopropylethylamine (0.47 mL, 2.72 mmol) at 25 °C and the resulting mixture was stirred at 130 °C for 3 h under Ar atmoshpere. After cooling to rt, the reaction mixture was diluted with water, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA/PE (0-80%) to afford the title compound (800 mg).

Step 2: 2-(2,6-dioxo-3-piperidyl)-5-[4-(piperazine-l -carbonyl)-! -piperidyl] isoindoline- 1,3-dione

To a solution of tert-butyl 4-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]- piperidine-4-carbonyl]piperazine- 1 -carboxylate (800 mg, 1.45 mmol) in anhydrous DCM (20 mL) was added HC1 solution in 1,4-dioxane (7.23 mL, 28.9 mmol, 20.0 eq) at 25 °C dropwise and the resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was then concentrated under reduced pressure and the residue was recrystallized from EtOAc to afford the title compound as HC1 salt (650 mg).

Step 3: tert-butyl (lR,5S)-3-(2-(((5S,7aS)-5-(((4-(l-(2-(2,6-dioxopiperidin-3-y l)-l,3-dioxoisoindolin- 5 -yl)piperidine-4-carbonyl)piperazine- 1 -carbonyl)oxy)methyl)-2-methylenetetrahydro- 1 H-pyrrolizin- 7a(5H)-yl)methoxy)-7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-f luoropyrido[4,3-d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1] octane-8-carboxylate To a solution of 2-(2,6-dioxo-3-piperidyl)-5-[4-(piperazine-l-carbonyl)-l-pip eridyl]- isoindoline- 1,3-dione (HC1 salt, 146 mg, 0.3 mmol), TEA (151 mg, 1.49 mmol) in anhydrous NMP (1.5 mL) was added a solution of tert-butyl (lR,5S)-3-(7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8- fluoro-2-(((5S,7aS)-2-methylene-5-((((4-nitrophenoxy)carbony l)oxy) methyl)tetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3, 8-diazabicyclo[3.2.1]octane-8- carboxylate (130 mg, 0.1488 mmol) in anhydrous THF (4.5 mL) at 25 °C and the resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was then added water and saturated NaHCCh aq. solution at 25 °C. The resulting mixture was stirred at 25 °C for 10 min. The mixture was extracted with EtoAc, washed with brine, dried over anhydrous NA ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH/DCM (0- 3%) to afford the title compound (110 mg).

Step 4: ((3S,7aS)-7a-(((4-((lR,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-methy lenehexahydro- 1 H- pyrrolizin-3-yl)methyl 4-(l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)p iperidine-4- carbonyl)piperazine- 1 -carboxylate

To a solution of tert-butyl (lR,5S)-3-(2-(((5S,7aS)-5-(((4-(l-(2-(2,6-dioxopiperidin-3-y l)-l,3- dioxoisoindolin-5 -yl)piperidine-4-carbonyl)piperazine- 1 -carbonyl)oxy) methyl)-2-methylenetetra- hydro- 1 H-pyrrolizin-7 a(5H)-yl)methoxy)-7 -(8-ethynyl-7 -fluoronaphthalen- 1 -yl)-8 -fluoropyri do- 14, 3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1] octane-8-carboxylate (110 mg, 0.092 mmol) in anhydrous DCM (10 mL) was added HC1 solution in 1,4-dioxane (4.0 M, 1.5 mL, 6.0 mmol) at -10 °C and the resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was then concentrated under reduced pressure and the residue was dissolved in DCM (10 mL). The mixture was basified by adding NH ₃ /McOH (0.5 mL) at -78 °C, and the resulting mixture was concentrated under reduced pressure. The residue was purified by Cl 8 column chromatography, eluted with MeCN/water (0-60%, 0.05% NH4HCO3) to afford the title compound (60.1 mg). MS (ES, m/z): [M+H] ⁺ = 1088.4. Example 49

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)o xy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl (8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)am ino)-8- oxooctyl)carbamate

Step 1: tert-butyl (8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl) amino)-8-oxooctyl)- carbamate

To a solution of 5-amino-2-(2,6-dioxo-3-piperidyl) isoindoline- 1,3 -di one (200 mg, 0.73 mmol) and 8-(tert-butoxycarbonylamino)octanoic acid (227.79 mg, 0.88 mmol) in anhydrous DMF (4 mL) was added NMI (420.64 mg, 5.12 mmol), followed by TCFH (616.1 mg, 2.2 mmol) at 25 °C under argon atmosphere and stirred for 3 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by Prep-HPLC (0~70% acetonitrile in water with 0.05% formic acid) to afford the title compound (200 mg). Step 2 : ((3S,7aS)-7a-(((4-((lR,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-methy lene hexahydro- lH-pyrrolizin-3-yl)methyl(8-((2-(2,6-dioxopiperidin-3-yl)-l, 3-dioxoiso indolin-5-yl)amino)-8- oxooctyl)carbamate The title compound was prepared by proceeding analogously as described in Example 48, Steps 2-4, using tert-butyl (8-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)am ino)-8- oxooctyl)carbamate instead of tert-butyl 4-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5- yl]piperidine-4-carbonyl]piperazine- 1 -carboxylate in Step 2. MS (ES, m/z): [M+H]+ =1049.4.

Example 50

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)o xy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3 -yl)methyl ( 1 -((4-((4-(3 -(2, 4-di oxotetrahydro pyrimidin- 1 (2H)-yl)- 1 -methyl- 1 H-indazol-

6-yl)piperidin- 1 -yl)methyl)phenyl)sulfonyl) piperidin-4-yl)carbamate

Step 1 : tert-butyl ( 1 -((3 -((4-(3 -(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)- 1 -methyl- 1 H-indazol-6-yl)- piperidin-l-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbama te

To a solution of l-(l-methyl-6-(piperidin-4-yl)-lH-indazol-3-yl)dihydro pyrimidine- 2,4(lH,3H)-dione (50 mg, 0.15 mmol, 1.00 eq.) and tert-butyl (l-((3-(bromomethyl)phenyl) sulfonyl)piperidin-4-yl)carbamate (99 mg, 0.23 mmol, 1.50 eq.) in THF (5.0 mL) was added TEA (45 mg, 0.45 mmol, 3.00 eq.) and the resulting mixture was stirred at 55 °C overnight. After cooling to rt, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM:MeOH=20: 1) to give the title compound.

Step 2 : 1 -(6-( 1 -(3-((4-aminopiperidin- 1 -yl)sulfonyl)benzyl)piperidin-4-yl)- 1 -methyl- 1 H-indazol-3 - yl)dihydropyrimidine-2,4(lH,3H)-dione

A mixture of tert-butyl (l-((3-((4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-meth yl-lH- indazol-6-yl)piperidin-l-yl)methyl)phenyl)sulfonyl)piperidin -4-yl)carbamate (50 mg, 0.07 mmol, 1.00 eq.) in TFA/DCM (0.5 mL/2.0 mL) was stirred at rt for 2 h. The mixture was concentrated to give the title compound (40 mg, crude).

Step 3: ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro- naphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)met hyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl ( 1 -((4-((4-(3 -(2,4-dioxotetrahydro pyrimidin- 1 (2H)-yl)- 1 -methyl- 1 H-indazol-

6-yl)piperidin- 1 -yl)methyl)phenyl)sulfonyl) piperidin-4-yl)carbamate

The title compound was prepared by proceeding analogously as described in Example 47, Steps 10 and 11, using l-(6-(l-(3-((4-aminopiperidin-l-yl)sulfonyl)benzyl)piperidin -4-yl)-l-methyl- lH-indazol-3-yl)dihydropyrimidine-2,4(lH,3H)-dione instead of 2-(2,6-dioxo-3-piperidyl)-5-[4-(4- piperidyl oxy)- l-piperidyl]isoindo line- 1,3-dione in Step 10. MS (ES, m/z): [M+H] ⁺ = 1214.5.

Example 51

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)o xy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl) piperazin-l- yl)methyl)piperidine- 1 -carboxylate The title compound was prepared by proceeding analogously as described in Example 47, Steps 10 and 11, using 2-(2,6-dioxo-3-piperidyl)-5-[4-(4-piperidylmethyl)piperazin- l-yl]isoindoline- 1, 3-dione (ref: WO2021/155321) instead of 2-(2,6-dioxo-3-piperidyl)-5-[4-(4-piperidyloxy)-l- piperidyl] isoindoline- 1,3-dione in Step 10. MS (ES, m/z): [M+H] ⁺ = 1074.5.

Example 52

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)o xy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl 4-(3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)propyl)piperidine- 1 -carboxylate

Step 1: tert-butyl 4-(3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl) amino) propyl)piperidine- 1 -carboxylate

A solution of tert-butyl 4-(3-aminopropyl)piperidine-l -carboxylate (242.17 mg, 1 mmol), 2- (2, 6-dioxopiperidin-3-yl)-5-fluoroisoindoline-l, 3-dione (276 mg, 1 mmol) and N,N-diisopropyl- ethylamine (0.52 mL, 3 mmol) in DMF (1 mL) was stirred for 12 h at 105 °C. After cooling to rt, water was added to the reaction mixture and the precipitates were isolated by filtration. The isolated solid was dissolved in DCM, dried over Na2SO4, and concentrated in vacuum. The residue was purified by silica gel column chromatography, eluted with EtOAc/PE = 0-50% to afford the title compound (120 mg).

Step 2: ((3S,7aS)-7a-(((4-((lR,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-methy lenehexahydro- 1 H-

yl)methyl 4-((4-(3 -(2, 4-dioxotetrahydropyrimidin- 1 (2H)-yl)- 1 -methyl- lH-indazol-6- yl)phenyl)sulfonyl)piperidine- 1 -carboxylate

Step 1: tert-butyl 4-((4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH -indazol-6- yl)phenyl)sulfonyl)piperidine- 1 -carboxylate

To a solution of l-(6-bromo-l-methyl-indazol-3-yl)hexahydropyrimidine-2, 4-dione (162 mg, 0.5 mmol) and tert-butyl 4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]sul fonyl- piperazine- 1 -carboxylate (249.46 mg, 0.55 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added CsF (114.22 mg, 0.75 mmol) and Pd(dppf)C12 (40.61 mg, 0.05 mmol) and the resulting mixture was stirred for 5 h at 85 °C. After coolin tot rt, the reaction was quenched by water, extracted with DCM, washed with brine, dried over Na2SO4, and concentrated in vacuum. The residue was purified by silica gel column chromatography, eluted with MeOH/DCM (0-6%) to afford the title compound (270 mg). Step 2: ((3S,7aS)-7a-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-e thynyl-7-fluoronaphthalen-l-yl)- 8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-6-methyleneh exahydro-lH-pyrrolizin-3-yl)methyl 4-((4-(3-(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)- 1 -methyl- 1 H-indazol-6-yl)phenyl)sulfonyl)- piperidine- 1 -carboxylate The title compound was prepared by proceeding analogously as described in Example 48, Steps 2-4, using : tert-butyl 4-((4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH -indazol- 6-yl)phenyl)sulfonyl)piperidine-l -carboxylate instead of tert-butyl 4-[l-[2-(2,6-dioxo-3-piperidyl)- 1 ,3 -dioxo-isoindolin-5-yl]piperidine-4-carbonyl]piperazine-l -carboxylate in Step 2. MS (ES, m/z): [M+H] ⁺ = 1102.4.

Example 55

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)o xy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl 4-(3-(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)- 1 -methyl- 1 H-indazol-6-yl)-

The title compound was prepared by proceeding analogously as described in Example 47, Steps 10 and 11, using l-(l-methyl-6-(piperidin-4-yl)-lH-indazol-3-yl)dihydropyrimi dine- 2,4(lH,3H)-dione (ref: WO2021/127561) instead of 2-(2,6-dioxo-3-piperidyl)-5-[4-(4-piperidyloxy)- l-piperidyl]isoindoline- 1,3-dione in Step 10. MS (ES, m/z): [M+H] ⁺ = 962.4.

Example 56

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)o xy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl (4-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)oxy)bu tyl)carbamate The title compound was prepared by proceeding analogously as described in Example 47, Steps 10 and 11, using 3-(5-(4-aminobutoxy)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione instead of 2- (2, 6-dioxo-3-piperidyl)-5-[4-(4-piperidyloxy)-l-piperidyl]isoin doline-l, 3-dione in Step 10. MS (ES, m/z): [M+H] ⁺ = 966.4.

Example 57

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)o xy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl 4-(2-(2,6-dioxopiperidin-3-yl)- 1 -oxoisoindolin-4-yl)piperidine- 1 -carboxylate

The title compound was prepared by proceeding analogously as described in Example 47, Steps 10 and 11, using 3 -(l-oxo-4-(piperidin-4-yl)isoindolin-2-yl)piperidine-2, 6-dione (ref:

WO20 17/197056) instead of 2-(2,6-dioxo-3-piperidyl)-5-[4-(4-piperidyloxy)-l-piperidyl] isoindoline- 1, 3-dione in Step 10. MS (ES, m/z): [M+H] ⁺ = 962.4.

Example 58

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)o xy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl 4-(2-(2,6-dioxopiperidin-3-yl)- 1 -oxoisoindolin-5-yl)piperidine- 1 -carboxylate

The title compound was prepared by proceeding analogously as described in Example 47, Steps 10 and 11, using 3-(l-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2, 6-dione (ref: WO2020/165833) instead of 2-(2,6-dioxo-3-piperidyl)-5-[4-(4-piperidyloxy)-l-piperidyl] isoindoline- 1, 3-dione in Step 10. MS (ES, m/z): [M+H] ⁺ = 962.4. Example 59

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)o xy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl 4-(3-(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)- 1 -methyl- 1 H-indazol-6-yl)- piperazine- 1 -carboxylate

The title compound was prepared by proceeding analogously as described in Example 47, Steps 10 and 11, using l-(l-methyl-6-(piperazin-l-yl)-lH-indazol-3-yl)dihydro pyrimidine- 2,4(lH,3H)-dione (ref: WO2021/127561) instead of 2-(2,6-dioxo-3-piperidyl)-5-[4-(4-piperidyloxy)- l-piperidyl]isoindoline- 1,3-dione in Step 10. MS (ES, m/z): [M+H] ⁺ = 963.4.

Example 60

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)o xy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl (2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)ethyl)(methyl)carbamate

The title compound was prepared by proceeding analogously as described in Example 47, Steps 10 and 11, using 2-(2,6-dioxo-3-piperidyl)-4-[2-(methylamino)ethylamino] isoindoline- 1,3- dione (ref: W02021/18018) instead of 2-(2,6-dioxo-3-piperidyl)-5-[4-(4-piperidyloxy)-l- piperidyl] isoindoline- 1,3-dione in Step 10. MS (ES, m/z): [M+H] ⁺ = 965.4. Example 61

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)o xy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl (4-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl )amino)-2- oxoethyl)cyclohexyl)carbamate

The title compound was prepared by proceeding analogously as described in Example 49, Steps 1-2, using 2-(4-((tert-butoxycarbonyl)amino)cyclohexyl)acetic acid instead of 8-(tert- butoxycarbonylamino)octanoic acid in Step 1.. MS (ES, m/z): [M+H] ⁺ = 1047.4.

Example 62

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)o xy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl 9-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)car bamoyl)-3- azaspiro[5.5]undecane-3-carboxylate

The title compound was prepared by proceeding analogously as described in Example 49, Steps 1-2, using 3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecane-9-carboxylic acid instead of 8-(tert- butoxycarbonylamino)octanoic acid in Step 1. MS (ES, m/z): [M+H] ⁺ = 1087.3.

Example 63

Synthesis of ((3S,7aS)-7a-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-e thynyl-7-fluoronaphthalen- l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-6-meth ylenehexahydro-lH-pyrrolizin-3- yl)methyl 4-((3-(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)- 1 -methyl- 1 H-indazol-6-yl)- ethynyl)piperidine- 1 -carboxylate

Step 1 : tert-butyl 4-((3 -(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)- 1 -methyl- 1 H-indazol-6-yl)ethynyl)- piperidine- 1 -carboxylate

To a mixture of l-(5-bromo-l-methyl-indazol-3-yl)hexahydropyrimidine-2, 4-dione (323 mg, 1.0 mmol), tert-butyl 4-ethynylpiperidine- 1 -carboxylate (418.39 mg, 2.mmol), Pd(PPh3)2C12 (70.16 mg, 0.1 mmol), and Cui (38.07 mg, 0.2 mmol) in DMF (2 mL), was added TEA (0.7 mL, 5.0 mmol) and the resulting mixture was stirred at 105 °C for 3 h under Ar atmosphere. After cooling to rt, the reaction mixture was quenched by water, extracted by DCM, washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuum to afford the title compound (420 mg).

Step 2: ((3S,7aS)-7a-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-e thynyl-7-fluoronaphthalen-l-yl)- 8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-6-methyleneh exahydro-lH-pyrrolizin-3-yl)methyl 4-((3-(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)- 1 -methyl- 1 H-indazol-6-yl)ethynyl)piperidine- 1 - carboxylate The title compound was prepared by proceeding analogously as described in Example 48, Steps 2-4, using tert-butyl 4-((3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l -methyl- lH-indazol-6- yl)ethynyl)piperidine-l -carboxylate instead of tert-butyl 4-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo- isoindolin-5-yl]piperidine-4-carbonyl]piperazine-l -carboxylate in Step 2. MS (ES, m/z): [M+H] ⁺ = 986.4.

Example 64

Synthesis of ((3S,7aS)-7a-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-e thynyl-7-fluoronaphthalen- l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-6-meth ylenehexahydro-lH-pyrrolizin-3- yl)methyl 4-(2-(3-(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)- 1 -methyl- 1 H-indazol-6- yl)ethyl)piperidine- 1 -carboxylate

Step 1 : tert-butyl 4-(2-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH- indazol-6-yl)ethyl)- piperidine- 1 -carboxylate

To a solution of tert-butyl 4-[2-[3-(2,4-dioxohexahydropyrimidin-l-yl)-l-methyl-indazol- 6- yl]-ethynyl]piperidine-l -carboxylate (120 mg, 0.27 mmol) in ethanol (2 mL) was added 10% Pd/C (20 mg) and ammonium formate (16.76 mg, 0.27 mmol) and the resulting mixture was stirred at 25 °C for 12 h. The reaction mixture was filtered and the filtrate was evaporated in vacuum. The residue was purified by silica gel column chromatography, eluted with MeOH/DCM (0-6%) to afford the title compound (120 mg).

Step 2: ((3S,7aS)-7a-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-e thynyl-7-fluoronaphthalen-l-yl)- 8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-6-methyleneh exahydro-lH-pyrrolizin-3-yl)methyl 4-(2-(3 -(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)- 1 -methyl- 1 H-indazol-6-yl)ethyl)piperidine- 1 - carboxylate

The title compound was prepared by proceeding analogously as described in Example 48, Steps 2-4, using tert-butyl 4-(2-(3 -(2, 4-dioxotetrahydropyrimi din- l(2H)-yl)-l -methyl- lH-indazol-6- yl)ethyl)piperidine-l -carboxylate instead of tert-butyl 4-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo- isoindolin-5-yl]piperidine-4-carbonyl]piperazine-l -carboxylate in Step 2. MS (ES, m/z): [M+H] ⁺ = 990.4.

Example 65

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)o xy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl 4-((l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl) piperidin-4-yl)-

The title compound was prepared by proceeding analogously as described in Example 47, Steps 10 and 11, using 2-(2,6-dioxo-3-piperidyl)-5-[4-(4-piperidylmethyl)-l-piperid yl]isoindoline- 1, 3-dione (ref: WO2022/120355) instead of 2-(2,6-dioxo-3-piperidyl)-5-[4-(4-piperidyloxy)-l- piperidyl] isoindoline- 1,3-dione in Step 10. MS (ES, m/z): [M+H] ⁺ = 1073.5.

Example 66

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)o xy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl (2-(l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl) piperidin-4- yl)ethyl)carbamate

The title compound was prepared by proceeding analogously as described in Example 47, Steps 10 and 11, using 5-[4-(2-aminoethyl)-l-piperidyl]-2-(2,6-dioxo-3-piperidyl) isoindoline- 1,3- dione (ref: WO2021/155321) instead of 2-(2,6-dioxo-3-piperidyl)-5-[4-(4-piperidyloxy)-l- piperidyl] isoindoline- 1,3-dione in Step 10. MS (ES, m/z): [M+H] ⁺ = 1019.4.

Example 67

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)o xy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl 4-((2-(2,6-dioxopiperidin-3-yl)- 1 ,3-dioxoisoindolin-5- yl)carbamoyl)piperidine- 1 -carboxylate

The title compound was prepared by proceeding analogously as described in Example 49, Steps 1-2, using l-tert-butoxycarbonylpiperidine-4-carboxylic acid instead of 8-(tert- butoxycarbonylamino)octanoic acid in Step 1. MS (ES, m/z): [M+H] ⁺ = 1019.4.

Example 68

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)o xy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl (4-(4-(3 -(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)- 1 -methyl- 1 H-indazol-6- yl)piperidine- 1 -carbonyl)cyclohexyl)carbamate

Step 1: tert-butyl (4-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH -indazol-6-yl)- piperidine- 1 -carbonyl)cyclohexyl)carbamate

A solution of HATU (116.14 mg, 0.31 mmol), N,N-diisopropylethylamine (0.08 mL, 0.46 mmol), 4-(tert-butoxycarbonylamino)cyclohexane-l -carboxylic acid (44.77 mg, 0.18 mmol), 1-[1- methyl-6-(4-piperidyl)indazol-3-yl]hexahydropyrimidine-2, 4-dione (50 mg, 0.15 mmol) in DMF (1 mL) was stirred at rt for 12 h. The reaction was quenched with water, extracted by EtOAc, washed with brine, dried overNa2 SO ₄ , and concentrated in vacuum. The residue was purified by column chromatography, eluted with MeOH/DCM (0-10%) to afford the title compound (76 mg).

Step 2: ((3S,7aS)-7a-(((4-((lR,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-methy lenehexahydro- 1 H- pyrrolizin-3-yl)methyl (4-(4-(3 -(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)- 1 -methyl- 1 H-indazol-6- yl)piperidine- 1 -carbonyl)cyclohexyl)carbamate

The title compound was prepared by proceeding analogously as described in Example 48, Steps 2-4, using tert-butyl (4-(4-(3 -(2, 4-dioxotetrahydropyrimi din- l(2H)-yl)-l -methyl- lH-indazol-6- yl)piperidine- 1 -carbonyl)cyclohexyl)carbamate instead of tert-butyl 4-[l-[2-(2,6-dioxo-3-piperidyl)- 1,3 -di oxo-isoindolin-5-yl]piperidine-4-carbonyl]piperazine-l -carboxylate in Step 2. MS (ES, m/z): [M+H] ⁺ = 1087.4. Example 69

Synthesis of ((3R,7aR)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)o xy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl 4-(4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l -methyl- lH-indazol-6-yl)- piperidine- 1 -carbonyl)piperidine- 1 -carboxylate

The title compound was prepared by proceeding analogously as described in Example 68, Steps 1-2, using l-tert-butoxycarbonylpiperidine-4-carboxylic acid instead of 4-(tert- butoxycarbonylamino)cyclohexane- 1 -carboxylic acid in Step 1. MS (ES, m/z): [M+H] ⁺ = 1074.2 Example 70

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)o xy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl 4-(4-((3 -(2,4-dioxotetrahydropyrimidin- 1 (2H)-yl)- 1 -methyl- 1 H-indazol-6- yl)amino)piperidine- 1 -carbonyl)piperidine- 1 -carboxylate

Step 1: tert-butyl 4-((3 -(2, 4-dioxotetrahydropyrimi din- l(2H)-yl)-l -methyl- 1 H-indazol-6-yl)amino)- piperidine- 1 -carboxylate A mixture of l-(6-bromo-l-methyl-lH-indazol-3-yl)dihydropyrimidine-2,4(lH ,3H)-dione (50 mg, 0.15 mmol, 1.0 eq), tert-butyl 4-aminopiperi dine- 1 -carboxylate (37.19 mg, 0.19 mmol, 1.2 eq), CS2CO3 (60.53 mg, 0.19 mmol, 1.2 eq), Brettphos (16.61 mg, 0.03 mmol, 0.03 eq) and Pd2(dba)3 (14.17 mg, 0.02 mmol, 0.1 eq) in 1,4-dioxane (1.0 mL) was stirred at 90 °C for 3 h under Ar2 atmosphere. After cooling to rt, the mixture was filtrated and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography, eluted with DCM/MeOH (0-5%) to afford the title compound (40 mg).

Step 2: l-(l-methyl-6-(piperidin-4-ylamino)-lH-indazol-3-yl)dihydrop yrimidine-2,4(lH,3H)-dione

To a solution of tert-butyl 4-((3-(2,4-dioxotetrahydropyrimidin- l(2H)-yl)-l -methyl- 1H- indazol-6-yl)amino)piperi dine- 1 -carboxylate (40 mg, 0.09 mmol, 1.0 eq) in EtOAc (1 mL) was added HC1 solution in EtOAc (2.0 M, 1 mL) at 25°C and the resulting mixture was stirred at 25°C for 1 h. The mixture was concentrated in reduced pressure to afford the title compound (30 mg). Step 3: tert-butyl 4-(4-((3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH -indazol-6- yl)amino)piperidine- 1 -carbonyl)piperidine- 1 -carboxylate

A mixture of l-(l-methyl-6-(piperidin-4-ylamino)-lH-indazol-3-yl)dihydro pyrimidine - 2,4(lH,3H)-dione (30 mg, 0.09 mmol , 1.0 eq), 1 -(tert-butoxycarbonyl) piperidine-4-carboxylic acid (22.10 mg, 0.10 mmol, 1.1 eq), 1 -methylimidazole (28.78 mg, 0.35 mmol, 4.0 eq) and TCFH (49.17 mg, 0.18 mmol, 2.0 eq) in DMF (1 mL) was stirred at 25 °C for 5 h. The mixture was quenched with water, extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue obtained was purified by column chromatography, eluted with DCM/MeOH (0-5%) to afford the title compound (35 mg). Step 4. ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro- naphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)met hyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl 4-(4-((3 -(2, 4-dioxotetrahydropyrimi din- l(2H)-yl)-l -methyl- lH-indazol-6- yl)amino)piperidine- 1 -carbonyl)piperidine- 1 -carboxylate

The title compound was prepared by proceeding analogously as described in Example 48, Steps 2-4, using tert-butyl 4-(4-((3 -(2, 4-dioxotetrahydropyrimi din- l(2H)-yl)-l -methyl- lH-indazol-6- yl)amino)piperi dine- 1 -carbonyl)piperidine- 1 -carboxylate instead of tert-butyl 4-[l-[2-(2,6-dioxo-3- piperidyl)-l,3-dioxo-isoindolin-5-yl]piperidine-4-carbonyl]p iperazine-l-carboxylate in Step 2. MS (ES, m/z): [M+H] ⁺ = 1088.4

Example 71

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)o xy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl 4-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl) oxy)piperidine-l- carbonyl)piperidine- 1 -carboxylate

Step 1: tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)oxy )piperidine-l- carboxylate

A mixture of PPI13 (393.25 mg, 1.5 mmol) tert-butyl 4-hydroxypiperi dine- 1 -carboxylate (0.38 mL, 2 mmol), DIAD (0.58 mL, 3 mmol) and 2-(2,6-dioxo-3-piperidyl)-5-hydroxy-isoindoline-l,3- dione (274.1 mg, 1 mmol) in THF (2 mL) was stirred at 25 °C for 12 h. The reaction mixture was diluted with water, extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (0-6%) to afford the title compound (230 mg).

Step 2: 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yloxy)isoindoline - 1,3-dione

To a solution of tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5- yl] oxypiperidine- 1 -carboxylate (230 mg, 0.50 mmol) in EtOAc (ImL), was added HC1 solution in EA (4.0 M, 1 mL) and the resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuum and the residue obtained was washed with EtOAc to afford the title compound (120 mg).

Step 3: tert-butyl 4-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl) oxy) piperidine- 1 - carbonyl)piperidine- 1 -carboxylate

A mixture of TEA (0.05 mL, 0.34 mmol), HATU (63.84 mg, 0.17 mmol), 2-(2,6-dioxo-3- piperidyl)-5-(4-piperidyloxy)isoindoline- 1,3-dione (40 mg, 0.11 mmol), 1 -tert-butoxycarbonyl piperidine-4-carboxylic acid (0.03 mL, 0.13 mmol) in DMF (1 mL) was stirred at 25 °C for 12 h. The reaction was quenched by water, extracted by EtOAc, dried over Na2SO4 and concentrated in vacuum. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (0-6%) to afford the title compound (35 mg).

Step 4: ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro- naphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)met hyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl 4-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl) oxy)piperidine-l- carbonyl)piperidine- 1 -carboxylate The title compound was prepared by proceeding analogously as described in Example 48, Steps 2-4, using tert-butyl 4-[4-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]ox ypiperidine-l- carbonyl]piperidine-l -carboxylate instead of tert-butyl 4-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo- isoindolin-5-yl]piperidine-4-carbonyl]piperazine-l -carboxylate in Step 2. MS (ES, m/z): [M+H] ⁺ = 1104.4

Example 72

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)o xy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3 -yl)methyl (3 -(4-(3 -(2,4-dioxotetrahydro pyrimidin- 1 (2H)-yl)- 1 -methyl- 1 H-indazol-6- yl)piperidine- 1 -carbonyl)cyclopentyl) carbamate

The title compound was prepared by proceeding analogously as described in Example 68, Steps 1-2, using 3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid instead of 4-(tert- butoxycarbonylamino)piperidine- 1 -carboxylic acid in Step 1. MS (ES, m/z): [M+H] ⁺ = 1073.5.

Example 73

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)o xy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl 3-(4-(3-(2,4-dioxotetrahydropyrimidin- l(2H)-yl)-l -methyl- lH-indazol-6- yl)piperidine- 1 -carbonyl)pyrrolidine- 1 -carboxylate The title compound was prepared by proceeding analogously as described in Example 68, Steps 1-2, using 1 -tert-butoxycarbonylpyrrolidine-3 -carboxylic acid instead of 4-(tert- butoxycarbonylamino)piperidine- 1 -carboxylic acid in Step 1. MS (ES, m/z): [M+H] ⁺ = 1060.2

Example 74

Synthesis of ((3R,7aR)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)o xy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl 3-(4-(3-(2,4-dioxotetrahydropyrimidin- l(2H)-yl)-l -methyl- lH-indazol-6- yl)piperidine- 1 -carbonyl)piperidine- 1 -carboxylate

The title compound was prepared by proceeding analogously as described in Example 68, Steps 1-2, using l-tert-butoxycarbonylpiperidine-3 -carboxylic acid instead of 4-(tert- butoxycarbonylamino)piperidine- 1 -carboxylic acid in Step 1. MS (ES, m/z): [M+H] ⁺ = 1073.5

Example 75

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)o xy)methyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl (2-(l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl) piperidine-4-

Step 1: methyl l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)pipe ridine-4-carboxylate

A solution of methyl piperidine-4-carboxylate (0.27 mL, 2 mmol), TEA (0.42 mL, 3.0 mmol) and 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline- 1,3-dione (276.09 mg, 1.0 mmol) in DMF (2mL) was heated at 120 °C for 1 h with microwave. After cooling to rt, the reaction mixture was diluted with water, extracted by EtOAc, dried over Na2SO4 and concentrated. The residue was purified by column chromatography, eluted with DCM/MeOH (0-10%) to afford the title compound (210 mg).

Step 2: l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)pipe ridine-4-carboxylic acid

A mixture of methyl 1-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]piper idine-4- carboxylate (100 mg, 0.25 mmol) and sulfuric acid (0.04 mL, 0.75 mmol) in water (2 mL) was stirred at 90 °C for 5 h. The reaction mixture was extracted by EtOAc, dried over Na2SO4 and concentrated to afford the title compound (96 mg).

Step 3: tert-butyl (2-(l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl) piperidine-4- carboxamido)ethyl)carbamate

A solution of TEA (0.04 mL, 0.26 mmol), tert-butyl N-(2-aminoethyl)carbamate (0.07 mL, 0.78 mmol), HATU (98.67 mg, 0.26 mmol) and l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5- yl]piperidine-4-carboxylic acid (96 mg, 0.2491 mmol) in DMF ( ImL) was stirred at 25 °C for 12 h. The reaction was quenched by water, extracted by EtOAc, washed with brine, dried over Na2SO4 and concentrated in vacuum. The residue was purified by column chromatography, eluted with DCM/MeOH (0-6%) to afford the title compound (50 mg).

Step 4: ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro- naphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)met hyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl (2-(l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl) piperidine-4- carboxamido)ethyl)carbamate

The title compound was prepared by proceeding analogously as described in Example 48, Steps 2-4, using tert-butyl (2-(l-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl) piperidine-4- carboxamido)ethyl)carbamate instead of tert-butyl 4-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo- isoindolin-5-yl]piperidine-4-carbonyl]piperazine-l -carboxylate in Step 2. MS (ES, m/z): [M+H] ⁺ = 1063.5.

Example 76

Synthesis of ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7- fluoronaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)o xy)methyl)-6-methylene hexahydro-

1 H-pyrrolizin-3 -yl)methyl 4-((4-(3 -(2 ,4-dioxotetrahydropyrimidin- 1 (2H)-yl)- 1 -methyl- 1 H-indazol-6- yl)piperidin- 1 -yl)sulfonyl)piperidine- 1 -carboxylate

Step 1: tert-butyl 4-((4-(3-(2,4-dioxotetrahydropyrimidin-l(2H)-yl)-l-methyl-lH -indazol-6- yl)piperidin- 1 -yl)sulfonyl)piperidine- 1 -carboxylate

A solution of l-[l-methyl-6-(4-piperidyl)indazol-3-yl]hexahydropyrimidine- 2, 4-dione (30 mg, 0.09 mmol), TEA (0.04 mL, 0.27 mmol) and tert-butyl 4-chlorosulfonylpiperidine- 1 -carboxylate (39 mg, 0.14 mmol) in DMSO (ImL) and THF (ImL) was stirred at 90 °C for 5 h. After cooling to rt, the reaction mixture was diluted with water, extracted by EtOAc, washed with brine, and evaporated in vacuum. The residue was purified by column chromatography, eluted with DCM/MeOH (0-8%) to afford the title compound (40 mg).

Step 2: ((3S,7aS)-7a-(((4-((lR,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl )-7-(8-ethynyl-7-fluoro- naphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)met hyl)-6-methylene hexahydro- 1H- pyrrolizin-3-yl)methyl 4-((4-(3 -(2, 4-dioxotetrahydropyrimi din- l(2H)-yl)-l -methyl- lH-indazol-6- yl)piperidin- 1 -yl)sulfonyl)piperidine- 1 -carboxylate

The title compound was prepared by proceeding analogously as described in Example 48, Steps 2-4, using tert-butyl 4-((4-(3 -(2, 4-dioxotetrahydropyrimi din- l(2H)-yl)-l -methyl- lH-indazol-6- yl)piperidin-l-yl)sulfonyl)piperidine-l -carboxylate instead of tert-butyl 4-[l-[2-(2,6-dioxo-3- piperidyl)-l,3-dioxo-isoindolin-5-yl]piperidine-4-carbonyl]p iperazine-l-carboxylate in Step 2. MS (ES, m/z): [M+H] ⁺ = 1110.4.

Example 501

Synthesis of ((3S,7aS)-7a-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-e thynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl 4-(4-(((S)-l-((2S,4R)-4-hydroxy-2-(((S)-l-(4-(4-methylthiazo l-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin- 1 -yl)-3 ,3-dimethyl- 1 -oxobutan-2-yl)carbamoyl)- 1 H- 1 ,2,3- triazol- 1 -yl)piperidine- 1 -carboxylate Step 1: tert-butyl 4-(4-(((S)-l-((2S,4R)-4-hydroxy-2-(((S)-l-(4-(4-methylthiazo l-5-yl)phenyl)- ethyl)carbamoyl)pyrrolidin- 1 -yl)-3 ,3 -dimethyl- 1 -oxobutan-2-yl)carbamoyl)- 1 H- 1 ,2,3-triazol- 1 -yl)- piperidine- 1 -carboxylate

A mixture of (2S,4R)-l-[(2S)-2-amino-3,3-dimethylbutanoyl]-4-hydroxy-N-[( lS)-l-(4-(4- methyl-l,3-thiazol-5-yl)phenyl)ethyl]pyrrolidine-2-carboxami de (0.1 g, 0.22 mmol), l-(l-[(tert- butoxy)carbonyl]piperidin-4-yl)-lH-l,2,3-triazole-4-carboxyl ic acid (0.098 g, 0.33 mmol), HATU (0.10 g, 0.26 mmol) and DIPEA (0.085 g, 0.66 mmol) in DMF (3 mL) was stirred at rt for 16 h. The reaction mixture was purified by reverse phase C18 column chromatography (10-100% MeOH/H ₂ O with 0.1% NH4HCO3] to give the title compound (0.11 g).

Step 2: N-((S)-l-((2S,4R)-4-hydroxy-2-(((S)-l-(4-(4-methylthiazol-5- yl)phenyl)ethyl)- carbamoyl)pyrro lidin- 1 -y 1) - 3 ,3 -dimethyl- 1 -oxobutan-2-yl)- 1 -(piperidin-4-yl)- 1 H- 1 ,2 ,3 -triazole-4- carboxamide

To a solution of tert-butyl 4-(4-{[(2S)-l-[(2S,4R)-4-hydroxy-2-{[(lS)-l-(4-(4-methyl-l,3 - thiazol-5 -yl)phenyl)ethyl] carbamoyl [pyrrolidin- 1 -yl] -3 ,3 -dimethyl- 1 -oxobutan-2-yl] carbamoyl} - 1 H- 1, 2, 3 -triazol- l-yl)piperidine-l -carboxylate (0.03 g, 0.041 mmol) in DCM (3 mL) was added a solution of HC1 in dioxane (4.0 M , 1.0 mL). The reaction mixture was stirred at rt for 3 h and then concentrated to give the title compound (0.025 g).

Step 3: ((3S,7aS)-7a-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-e thynyl-7-fluoro-3-hydroxy- naphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)met hyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl 4-(4-(((S)-l-((2S,4R)-4-hydroxy-2-(((S)-l-(4-(4-methylthiazo l-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin- 1 -yl)-3 ,3-dimethyl- 1 -oxobutan-2-yl)carbamoyl)- 1 H- 1 ,2,3- triazol- 1 -yl)piperidine- 1 -carboxylate

The title compound was prepared by proceeding analogously as described in Example 1 , Steps 11 and 12, using N-((S)-l-((2S,4R)-4-hydroxy-2-(((S)-l-(4-(4-methylthiazol-5- yl)phenyl)ethyl)- carbamoyl)pyrro lidin- 1 -y 1) - 3 ,3 -dimethyl- 1 -oxobutan-2-yl)- 1 -(piperidin-4-yl)- 1 H- 1 ,2 ,3 -triazole-4- carboxamide instead of 4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopipe ridin-3- yl)isoindoline- 1,3-dione in Step 11. MS (ESI) m/z = 637.1 [(M+2)/2] ⁺ .

Example 502

Synthesis ((3S,7aS)-7a-(((4-((lR,5R)-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-methy lenehexahydro-

1 H-pyrrolizin-3 -yl)methyl 4-((l-((S)-3 -((2 S,4R)- l-((S)-2-(l -fluorocyclopropane- 1 -carboxamido)-3 ,3 - dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-( 4-methylthiazol-5- yl)phenyl)propanoyl)piperidin-4-yl)methyl)piperidine-l -carboxylate Step 1: tert-butyl 4-((l-((S)-3-((2S,4R)-l-((S)-2-(l-fluorocyclopropane-l-carbo xamido)-3,3- dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-( 4-methylthiazol-5-yl)phenyl)- propanoyl)piperidin-4-yl)methyl)piperidine- 1 -carboxylate

To a solution of (S)-3-((2S,4R)-l-((S)-2-(l-fluorocyclopropane-l-carboxamido) -3,3- dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-( 4-methylthiazol-5-yl)phenyl)- propanoic acid (synthesized as described in WO2021222114A1) (176 mg, 626 pmol) and tert-butyl 4- (piperidin-4-ylmethyl)piperi dine- 1 -carboxylate in DCM (5 mL) was added TEA (158 mg, 1.57 mmol) and HATU (238 mg, 626 pmol). The resulting mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with DCM, washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography to give the title compound (430 mg).

Step 2: ((3S,7aS)-7a-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-e thynyl-7-fluoro-3-hydroxy- naphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)met hyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl 4-((l -((S)-3-((2S,4R)-l-((S)-2-(l -fluorocyclopropane- l-carboxamido)-3, 3- dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-( 4-methylthiazol-5-yl)phenyl)- propanoyl)piperidin-4-yl)methyl)piperidine- 1 -carboxylate

The title compound was prepared by proceeding analogously as described in Example 501, Steps 2 and 3, using tert-butyl 4-((l-((S)-3-((2S,4R)-l-((S)-2-(l-fluorocyclopropane-l-carbo xamido)- 3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3- (4-(4-methylthiazol-5-yl)phenyl)- propanoyl)piperidin-4-yl)methyl)piperidine-l -carboxylate instead of tert-butyl 4-(4-(((S)-l-((2S,4R)- 4-hydroxy-2-(((S)- 1 -(4-(4-methylthiazol-5-yl)phenyl)ethyl)carbamoyl)pyrrolidin- 1 -yl)-3,3-dimethyl- l-oxobutan-2-yl)carbamoyl)-lH-l, 2, 3 -triazol- l-yl)piperi dine- 1 -carboxylate in Step 2. MS (ESI) m/z = 695.6 [(M+2)/2] ⁺ . Example 503

Synthesis of ((3S,7aS)-7a-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-e thynyl-7-fluoro-3- hydroxynaphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl) oxy)methyl)-6-methylenehexahydro- lH-pyrrolizin-3-yl)methyl 4-(l-((S)-l-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin- 1 -yl)-3-methyl- 1 -oxobutan-2-yl)- 1 H- 1 ,2,3-triazol-4-yl)piperidine- 1 -

Step 1 : (2S,4R)- 1 -(L-valyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrro lidine-2-carboxamide

Tert-butyl ((S)-l-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl )carbamoyl)- pyrrolidin- 1 -yl)-3 -methyl- l-oxobutan-2-yl)carbamate (900 mg, 1.74 mmol) was added to a solution of HC1 in dioxane (4.0 M, 10.0 mL) and the resulting solution stirred at 20 °C for 0.5 h. The reaction mixture was concentrated to give the title compound (780 mg).

Step 2: (2S,4R)-l-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-(4-(4-m ethylthiazol-5-yl)benzyl)- pyrrolidine-2-carboxamide

To a solution of (2S,4R)-l-(L-valyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)ben zyl)- pyrrolidine-2-carboxamide (820 mg, 1.81 mmol) in MeOH (10 mL) was added K2CO3 (1.13 g, 8.15 mmol) and CUSO4.5H2O (45.2 mg, 181 pmol). IH-imidazole-l -sulfonylazide hydrochloride (759 mg, 3.62 mmol) was then added dropwise to the above mixture and the resulting mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with H2O, extracted with EA, washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (PE/EA = 1/0 to

0/1) to give the title compound (500 mg).

Step 2: tert-butyl 4-(l-((S)-l-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)b enzyl)carbamoyl)- pyrro lidin- 1 -yl)-3 -methyl- 1 -oxobutan-2-yl)- 1 H- 1 ,2,3-triazol-4-yl)piperidine- 1 -carboxylate

A mixture of (2S,4R)-l-((S)-2-azido-3-methylbutanoyl)-4-hydroxy-N-(4-(4-m ethylthiazol-5- yl)benzyl)pyrrolidine-2-carboxamide (100 mg, 226 pmol), tert-butyl 4-ethynylpiperidine- 1 - carboxylate, CUSO4.5H2O (10.3 mg, 56.5 pmol), sodium ascorbate (17.9 mg, 90.4 pmol) in t-BuOH (0.5 mL) and H2O (0.5 mL) was stirred at 20 °C for 12 h under N2. The reaction mixture was diluted with H2O, extracted with EA, washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to give the title compound (115 mg).

Step 3: ((3S,7aS)-7a-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-e thynyl-7-fluoro-3-hydroxy- naphthalen-l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)met hyl)-6-methylenehexahydro-lH- pyrrolizin-3-yl)methyl 4-(l-((S)-l-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)b enzyl)- carbamoyl)pyrrolidin- 1 -yl)-3 -methyl- 1 -oxobutan-2-yl)- 1 H- 1 ,2,3-triazol-4-yl)piperidine- 1 -carboxylate

The title compound was prepared by proceeding analogously as described in Example 501, Steps 2 and 3, using tert-butyl 4-(l-((S)-l-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5- yl)benzyl)carbamoyl)pyrrolidin- 1 -yl)-3-methyl- 1 -oxobutan-2-yl)- 1H- 1 ,2,3-triazol-4-yl)piperidine- 1 - carboxylate instead of tert-butyl 4-(4-(((S)-l-((2S,4R)-4-hydroxy-2-(((S)-l-(4-(4-methylthiazo l-5- yl)phenyl)ethyl)carbamoyl)pyrrolidin- 1 -yl)-3 ,3-dimethyl- 1 -oxobutan-2-yl)carbamoyl)- 1 H- 1 ,2,3- triazol- 1 -yl)piperi dine- 1 -carboxylate in Step 2. MS (ESI) m/z =601.7 [(M+2)/2] ⁺ .

Example 504 Synthesis of ((3S,7aS)-7a-(((4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-e thynyl-7-fluoronaphthalen- l-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl)oxy)methyl)-6-meth ylenehexahydro-lH-pyrrolizin-3- yl)methyl 4-(( 1 -((S)-3-((2S,4R)- 1 -((S)-2-( 1 -fluorocyclopropane- 1 -carboxamido)-3 ,3- dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)-3-(4-( 4-methylthiazol-5- yl)phenyl)propanoyl)piperidin-4-yl)methyl)piperidine-l -carboxylate

The title compound was prepared by proceeding analogously as described in Example 47, Steps 10 and 11, using (2S,4R)-l-((S)-2-(l-fluorocyclopropane-l-carboxamido)-3,3-di methyl- butanoyl)-4-hydroxy-N-((S)-l-(4-(4-methylthiazol-5-yl)phenyl )-3-oxo-3-(4-(piperidin-4-yl- methyl)piperidin-l-yl)propyl)pyrrolidine-2-carboxamide instead of 2-(2,6-dioxo-3-piperidyl)-5-[4-(4- piperidyloxy)- l-piperidyl]isoindoline- 1,3-dione in Step 10. MS (ESI) m/z = 723.3 [(M+2)/2] ⁺ .

Compounds 505-533 in Compound Table 2 were prepared by proceeding analogously as described in

Example 501, using acids in table below instead of l-(l-[(tert-butoxy)carbonyl]piperidin-4-yl)-lH- l,2,3-triazole-4-carboxylic acid in Example 501, Step 1.

Compounds 505, 515, 534 in Compound Table 2 were prepared by proceeding analogously as described in Example 501 Step 1-3, using acids in table below instead of l-(l-[(tert- butoxy)carbonyl]piperidin-4-yl)-lH-l,2,3-triazole-4-carboxyl ic acid in Example 501, step 1 and tert- butyl 3-(7-(8-ethynyl-7-fluoronaphthalen-l-yl)-8-fluoro-2-(((5S,7a S)-2-methylene-5-((((4- nitrophenoxy)carbonyl)-oxy)methyl)tetrahydro-lH-pyrrolizin-7 a(5H)-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylat e instead of tert-butyl 3-(7-(8-ethynyl-7- fluoro-3-(methoxymethoxy)naphthalen- 1 -yl)-8-fluoro-2- { [(2S,4R)- 1 -methyl-4- {[(4- nitrophenoxy)carbonyl]oxy}pyrrolidin-2-yl]methoxy}pyrido[4,3 -d]pyrimidin-4-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate in Example 501, step 3.

Compounds 514, 525, 535 in Compound Table 2 were prepared by proceeding analogously as described in Example 502, step 1 and 2, using amines in table below instead of tert-butyl 4-(piperidin- 4-ylmethyl)-piperidine- 1 -carboxylate in step 1.

Biological Examples

Example 1 AGS 3D Spheroid Cell Proliferation Assays

AGS cells were seeded into 96-well round black/clear bottom, ultra-low attachment surface plate in 100 pl cell culture medium (RPMI1640 with 10% FBS). After 3 days incubation at 37 °C and 5% CO2, compounds solubilized in DMSO were added by Tecan D300e dispenser (0.5% DMSO final). The cells were incubated for 4 days at 37 °C and 5% CO2. Cell proliferation was quantitated by addition of 50 pl/well of CellTiter-Glo® 3D reagent (Promega). The solutions were well mixed by shaking the plate for 10 minutes using an orbital plate shaker and then incubated at room temperature for a total of 30 minutes. After incubation, luminescence was then measured on a EnVision multimode plate reader (PerkinElmer). The results were normalized to percentage inhibition with DMSO control as 0% inhibition. The normalized luminescence results were plotted against compound concentration, and the data fit to 4-Parameter Logistic Model to calculate the EC50 by XLfit 5.5.0.

AspC-1 3D Spheroid Cell Proliferation Assays

AspC- 1 cells were seeded into 96-well round black/clear bottom, ultra-low attachment surface plate in 100 pl cell culture medium (RPMI1640 with 10% FBS). After 3 days incubation at 37 °C and 5% CO2, compounds solubilized in DMSO were added by Tecan D300e dispenser (0.5% DMSO final). The cells were incubated for 4 days at 37 °C and 5% CO2. Cell proliferation was quantitated by addition of 50 pl/well of CellTiter-Glo® 3D reagent (Promega). The solutions were well mixed by shaking the plate for 10 minutes using an orbital plate shaker and then incubated at room temperature for a total of 30 minutes. After incubation, luminescence was then measured on a EnVision multimode plate reader (PerkinElmer). The results were normalized to percentage inhibition with DMSO control as 0% inhibition. The normalized luminescence results were plotted against compound concentration, and the data fit to 4-Parameter Logistic Model to calculate the EC50 by XLfit 5.5.0.

Table 5. Inhibitory activity in AspC-1 3D spheroid cell proliferation assay.

A: Less than 0.1 uM

B: 0.1 uM ~ 1.0 uM

C: >1.0 uM ~ 10 uM

D: > 10 uM

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.

Ingredient Quantity per tablet (mg) compound Formula (IA) or (I) 400 cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5 Capsule Formulation

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

Ingredient Quantity per capsule (mg) compound Formula (IA) or (I) 200 lactose spray dried 148 magnesium stearate 2

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 incorporated 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.