Background The Rearranged during transfection (RET) kinase is a single-pass transmembrane 5 receptor belonging to the tyrosine kinase superfamily that is required for normal development, maturation, and maintenance of several tissues and cell types. The extracellular portion of the RET kinase contains four calcium-dependent cadherin-like repeats involved in ligand binding and a juxtamembrane cysteine-rich region necessary for the correct folding of the RET extracellular domain, while the cytoplasmic portion of 10 the receptor includes two tyrosine kinase sub domains. RET signaling is mediated by the binding of a group of 3 5 soluble proteins of the glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs), which also includes neurturin (NTRN), artemin (ARTN), and persephin (PSPN). Unlike other receptor tyrosine kinases, RET does not directly bind to GFLs and requires an additional 15 co-receptor, which can be one of four GDNF family receptor-a (GFRa) family members that are tethered to the cell surface by a glycosylphosphatidylinositollinkage. GFLs and GFRa family members form binary complexes that in tum bind to RET and recruit it into cholesterol-rich membrane subdomains where RET signaling occurs. Upon binding of the ligand-co-receptor complex, RET dimerization and 20 autophosphorylation on intracellular tyrosine residues recruits adaptor and signaling proteins to stimulate multiple downstream pathways. Adaptor protein binding to these docking sites leads to activation ofRas-MAPK and PBK-Akt/mTOR signaling pathways or to recruitment of the CBL family ofubiquitin ligases that functions in RET downregulation of the RET -mediated functions. 25 Disruptions in normal RET activity due to abnormal RET expression stemming from genetic alterations in the RET kinase, including protein-gene fusions and activating point mutations, lead to overactive RET signaling and uncontrolled cell growth, e.g., various cancer types and certain gastrointestinal disorders such as irritable bowel syndrome (IBS). The ability to inhibit abnormal RET activity in patients with cancer or 30 other disorders related to overactive RET signaling would be of great benefit to those patients. Additionally, some RET kinase genetic alterations are altering the 5 wo 2021/222017 PCT/US2021/028836 -2- conformational structure of a RET kinase to such an extent that a given RET kinase inhibitor may be less effective (or ineffective). In such cases, new RET kinase inhibitors that are effective to the modified RET kinase would greatly benefit patients. Summary Compounds of the formula: (I), 10 pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, are provided herein. In formula (I), A can be a five- or six-member aryl or heteroaryl; R1 can be hydrogen, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, -(Co-C4 alkyl)(Cs-C6 heteroalkyl), -(Co-C4 alkyl)(C3-C7 cycloalkyl), -(Co-C4 heteroalkyl)(C3-C7 cycloalkyl), -(Co-C4 alkyl)(C4-C7 cycloheteroalkyl), -(Co-C4 heteroalkyl)(C3-C7 cycloheteroalkyl), -(Co-C4 15 alkyl)(C4-C10 bicyclic), -(Co-C4 alkyl)(Cs-C6 aryl), -(Co-C4 alkyl)(Cs-C6 heteroaryl), -(CoC4 alkyl)(C4-C10 heterobicyclic), Cs-C12 spirane, Cs-C12 heterospirane, adamantane, difluoromethylsulfane, or pentafluorosulfane, wherein each R1 is optionally substituted with one or more groups that are independently halogen, cyano, hydroxyl, oxo, methyl, methoxy, hydroxymethyl, ethyl, ethoxy, hydroxyethyl, methylamine, N,N- 20 dimethylmethylamine, or mono-, di-, or tri-halomethyl, and wherein two R1 groups can fuse to form a ring structure that includes a portion of A and is optionally aromatic, and n is 1, 2, 3, 4 or 5; X1, X2, X3, and X4 each can be independently N, CH, C-CH3, C-CH2- 0H, C-OCH3, C-CH2-0CH3 or C-halogen; and R2 can be C1-C4 alkyl, -(Co-C4 alkyl)(C3- C7 cycloalkyl), -(Co-C4 alkyl)(C4-C7 heterocycloalkyl), -(Co-C4 alkyl)(C4-C10 bicyclic), 25 with each being optionally substituted with one or more groups that are independently deuterium, halogen, cyano, hydroxyl, oxo, methyl, methoxy, hydroxymethyl, ethyl, ethoxy, hydroxyethyl, cyclopropyl, or mono-, di-, or tri-halomethyl. The compounds of 5 wo 2021/222017 PCT/US2021/028836 -3- formula (I) contain a chiral center providing an R-enantiomeric form and an Senantiomeric form as shown here: (R-enantiomer) (S-enantiomer) (II) (III) 10 The R-enantiomer and S-enantiomer, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, in which A, R1, n, X1, X2, X3, X4, and R2 are defined herein are also provided. It is understood that formulas II and III are subspecies of formula I, and thus, references to formula I throughout this application also apply to formulas II and III. 15 Methods of using the compounds of formulas I, II, or III, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, to treat cancer, in particular for the treatment of cancer with abnormal RET expression (e.g., a RETassociated cancer like medullary thyroid cancer or RET fusion lung cancer) are also provided. The methods include administering a therapeutically effective amount of a 20 compound of formulas I, II, or III, or a pharmaceutically acceptable salt thereof, to a patient in need. Also provided herein, are compounds of formulas I, II, and III, and pharmaceutically acceptable salts thereof, for use in therapy. Further provided herein, are wo 2021/222017 PCT/US2021/028836 -4- the compounds of formulas I, II, and III, and pharmaceutically acceptable salts thereof, for use in the treatment of cancer, in particular for use in the treatment of cancer with abnormal RET expression (e.g., a RET -associated cancer like medullary thyroid cancer or RET fusion lung cancer). The use of compounds of formulas I, II, and III, or 5 pharmaceutically acceptable salts thereof, in the manufacture of a medicament for treating cancer, in particular for use in the treatment of cancer with abnormal RET expression (e.g., a RET-associated cancer like medullary thyroid cancer or RET fusion lung cancer), is also provided. 10 Description Novel RET kinase inhibitor compounds are described herein. These new compounds could address the need for potent, effective treatment of disorders associated with abnormal RET activity, e.g., IBS or cancer, especially cancer stemming from overactive RET signaling (i.e., RET -associated cancers). More specifically, these new 15 compounds could address the need for potent, effective treatment of RET-associated cancers such as lung cancer (e.g., small cell lung carcinoma or non-small cell lung carcinoma), thyroid cancer (e.g., papillary thyroid cancer, medullary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, or refractory differentiated thyroid cancer), thyroid ademona, endocrine gland neoplasms, lung adenocarcinoma, bronchioles 20 lung cell carcinoma, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), pheochromocytoma, parathyroid hyperplasia, breast cancer, mammary cancer, mammary carcinoma, mammary neoplasm, colorectal cancer (e.g., metastatic colorectal cancer), papillary renal cell carcinoma, ganglioneuromatosis of the gastroenteric mucosa, inflammatory myofibroblastic tumor, or cervical cancer. 25 The compounds described herein are compounds of formula (I): (I), or pharmaceutically acceptable salts thereof In formula (I), wo 2021/222017 PCT/US2021/028836 -5- A is a five- or six-member aryl or heteroaryl; Each R1 can be attached to A at various chemically appropriate positions and is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, -(Co-C4 alkyl)(Cs-C6 heteroalkyl), -(Co-C4 alkyl)(C3-C7 cycloalkyl), -(Co-C4 heteroalkyl)(C3-C7 cycloalkyl), 5 -(Co-C4 alkyl)(C4-C7 cycloheteroalkyl), -(Co-C4 heteroalkyl)(C3-C7 cycloheteroalkyl), -(Co-C4 alkyl)(C4-Cw bicyclic), -(Co-C4 alkyl)(Cs-C6 aryl), -(Co-C4 alkyl)(Cs-C6 heteroaryl), -(Co-C4 alkyl)(C4-C10 heterobicyclic), Cs-C12 spirane, Cs-C12 heterospirane, adamantane, difluoromethylsulfane, or pentafluorosulfane, wherein each R1 is optionally substituted with one or more groups that are independently halogen, cyano, hydroxyl, 10 oxo, methyl, methoxy, hydroxymethyl, ethyl, ethoxy, hydroxyethyl, methylamine, N,Ndimethylmethylamine, or mono-, di-, or tri-halomethyl, and wherein two R1 groups can fuse to form a ring structure that includes a portion of A and is optionally aromatic, and n is 1, 2, 3, 4, or 5; X1, X2, X3, and X4 are each independently N, CH, C-CH3, C-CH2-0H, C-OCH3, 15 C-CH2-0CH3 or C-halogen; and R2 is C1-C4 alkyl, -(Co-C4 alkyl)(C3-C7 cycloalkyl), -(Co-C4 alkyl)(C4-C7 heterocycloalkyl), -(Co-C4 alkyl)(C4-C10 bicyclic) each optionally substituted with one or more groups that are independently deuterium, halogen, cyano, hydroxyl, oxo, methyl, methoxy, hydroxymethyl, ethyl, ethoxy, hydroxyethyl, cyclopropyl, or mono-, di-, or tri- 20 halomethyl. While n is defined as 1, 2, 3, 4, or 5, some A-rings have 5 positions that may accommodate an R1 group, while others do not. For example, phenyl has 5 substitutable positions, pyrazoles have three substitutable positions, while an isoxazole has only two. Thus, the maximum value of the variable n can depend on the identity of the A-ring. 25 The specific chemical naming conventions used herein are intended to be familiar to one of skill in the chemical arts. Some terms are defined specifically for additional clarity. As used herein, the term alkyl means saturated linear or branched-chain monovalent hydrocarbon radicals of one to four atoms, e.g., "C1-C4 alkyl." In cases 30 where a zero is indicated, e.g., Co-C4 alkyl, this component of the substituent group can be absent, thus, if a Cs heterocycloalkyl substituent is at the R2 position in formula (I), the Cs heterocycloalkyl substituent would be described by the -(Co-C4 alkyl)(C4-C7 wo 2021/222017 PCT/US2021/028836 -6- heterocycloalkyl) substituent as described for R2 (i.e., the substituent group would be - (Co)(Cs heterocycloalkyl). Examples include, but are not limited to, methyl, ethyl, propyl, 1-propyl, isopropyl, and butyl. Similarly, as used herein, the term heteroalkyl means saturated linear or branched-chain monovalent alkyl molecules as defined herein 5 containing one or more heteroatoms that have replaced carbon(s) in the alkyl chain. As used herein, the term Cs-C6 aryl refers to a functional group or substituent derived from an aromatic ring containing five to seven carbon atoms and no heteroatoms. As used herein, the term Cs-C6 heteroaryl refers to a functional group or substituent derived from an aromatic ring containing carbon atoms and one or more heteroatoms 10 (e.g., nitrogen, oxygen, or sulphur) as part of the aromatic ring such that that ring contains from five to seven atoms. Examples of aryl and heteroaryl groups include, but are not limited to, benzene, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, and thiazole. As used herein, the term C3-C7 cycloalkyl means a cyclic alkyl molecule 15 containing three to seven carbon atoms. Examples of C3-C7 cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, and cyclopentyl. Similarly, as used herein, the term C4-C7 cycloheteroalkyl means a cycloalkyl molecule as defined herein, containing four to seven total atoms and including one or more hetero atoms that have replaced carbon(s) in the cycloalkyl chain. 20 As used herein, the term C4-C10 bicyclic refers to a group having two or more fused or bridged rings made from four to ten carbon atoms. When the C4-C10 bicyclic group is fused, the two rings share two adjacent atoms. When the C4-C10 bicyclic group is bridged, the two rings share three or more atoms. Bicyclic molecules can be all aliphatic, all aromatic, or mixed aromatic and aliphatic. The term C4-C10 heterobicyclic 25 refers to C4-C10 bicyclic groups as defined that also include one or more hetero atoms. Examples ofbridged C4-Cs bicycloalkyl molecules useful with the compounds of formula (I) include, but are not limited to: t-V- 3-methyl-bicyclo[l.l.l]pentyl, and t----0-cF3 3-(trifluoromethyl)-bicyclo[1.1.1 ]pentyl. wo 2021/222017 PCT/US2021/028836 -7- As used herein, the term Cs-C12 spirane refers to a group having two or more rings made from seven to twelve carbon atoms connected through a single common carbon atom. Similarly, the term Cs-C12 heterospirane refers to a group having two or more rings 5 made from seven to twelve atoms including carbon and at least one hetero atom joined by a spirocyclic linkage through a carbon atom, wherein each ring has three to six ring atoms (with one carbon atom being common to both rings), and wherein two of the ring atoms are nitrogen atoms. Examples of Cs-C 12 spiranes and heterospiranes useful with the compounds of formula (I) include, but are not limited to: 10 15 t-O<>= a ~OH ~OH ~N;( D()- spiro[3 .3 ]heptanyl, spiro[3 .3 ]heptan-2-onyl, spiro[3 .3 ]heptan-2-olyl, 2-methy 1 spiro[3. 3 ]heptan-2-ol y 1, 7-methyl-7-azaspiro[3.5]nonanyl, and 8-methyl-8-azaspiro[ 4.5]decanyl. As used herein, the term halogen means fluoro (F), chloro (Cl), bromo (Br), or iodo (I). As used herein, the term oxo means an oxygen that is double-bonded to a carbon 20 atom. In the compounds of formula (I), A-(R1)n can be 5 10 wo 2021/222017 PCT/US2021/028836 -8- wherein a wavy line indicates the connection point of A to the backbone as shown in formula (I). wO In one embodiment, in the compounds offormula (I), A-(R1)o is ~(R,), 0-N ~ In an embodiment, in the compounds of formula (I), A-(R1)n is (R1)n In another embodiment, in the compounds of formula (I), A-(R1)n is N RR' halogen . In a preferred embodiment, the halogen is F or Cl. In yet another embodiment, in the compounds of formula (I), A-(R1)n is In another embodiment, in the compounds of formula (I), A-(R1)n can be or H1 r ! N~ N~ .,__,..,..~ \4\ ,Yll t {R~b In an embodiment, in the compounds of formula (I), A-(R1)n is ; and n is 1. wo 2021/222017 PCT/US2021/028836 -9- In a further embodiment, in the compounds of formula (I), A-(R1)n is CH3 I ~~NdR1 or~ In an embodiment, A-(R1)n is a phenyl substituted with (R1)n. In a further embodiment, n is 1-4, or 1-3, or 1-2, or 1, or 2, or 2-4, or 2-5. In some embodiments 5 when A-(R1)n is a phenyl substituted with (R1)n, two R1 groups fuse to form a ring structure that includes a portion of A and is optionally aromatic, the resulting A-ring is optionally substituted, as described herein. 10 15 In some embodiments, in the compounds of formula (I), each R1 is independently selected from the group consisting ofH, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, In further embodiments, in the compounds of formula (I), at least one R1 group is H orCH3. In another embodiment, in the compounds of formula (I), at least one R1 is halogen, t-O< , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl,- , or CF3. In yet another embodiment, at least one R1 is halogen, -CH2C(CH3)3, In still yet another embodiment, at least one R1 is CH3, -CH2C(CH3)3, 20 -C(CH3)2CF3, C(CH3)2CH2CH3, -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, or CF3. In another embodiment, at least one R1 is an optionally substituted Cs-C12 spirane. In still another embodiment, at least one R1 is difluoromethylsulfane, or pentafluorosulfane. wo 2021/222017 PCT/US2021/028836 -10- In yet still another embodiment, at least one R1 is 2-fluoro-4-chlorophenyl; 2- chl oro-4-fl uoropheny 1; 2, 4-di chl oropheny 1; or 2, 4-difl uoropheny 1. In the compounds of formula (I), R2 can be "to or \ where 5 the wavy line indicates connection the backbone. 10 15 20 In some embodiments, in the compounds of formula (I), R2 is -CH(CH3)2,- ' ~"'· f-r-~ CH(CF3)CH3, -CH(CH3)CHF2, or In other embodiments, in the compounds of formula (I), R1 is "2( or y . In another embodiment, in the compounds offormula (I), R1 is "2( . In still another embodiment, in the compounds of formula (!), R1 is y . In some embodiments, in the compounds of formula (I), R2 is deuterated, i.e., it contains at least one deuterium. In some further embodiments, deuterated R2 is - CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2, orCD( CH3 )CD3. In some embodiments, R2 is -CH(CD3)2. In various embodiments, X1, X2, X3, and X4 are CH. In other embodiments, X1, X2, X3, and X4 are each independently CH, C-CH3, CCH2- 0H, C-OCH3, C-CH2-0CH3 or C-halogen, wherein at least one of X1, X2, X3, and X4 is notCH. In some embodiments, two of X1, X2, X3, and X4 are CH, while the other two are C-halogen. In a further embodiment, X1 and X2 are CF, and X3 and X4 are CH. In various embodiments, three of X1, X2, X3, and X4 are CH, while one is Chalogen. In a further embodiment, X2 is CF, while X1, X3 and X4 are CH. In still other embodiments, one of X1, X2, X3, and X4 is N. 5 10 wo 2021/222017 PCT/US2021/028836 -11- In a further embodiment, X2 is Nand at least two ofX1, X3, and X4 is CH. In a still further embodiment, X1 is N and at least two of X2, X3, and X4 is CH. In all of the above embodiments, it is understood that the definitions of variables apply to the non-salt forms "or a pharmaceutically acceptable salt thereof" One of skill in the art will appreciate that compounds as described by formula (I), or pharmaceutically acceptable salts thereof, contain at least one chiral center, the position of which is indicated by an - CH2C(CH3)3, -C(CH3)2CF3, , , and . In a further aspect, in the compounds of formulas (I), (II) and/or (III), R2 is - CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2, orwO CD(CH1)CD\ X1, X2, X1, and X4 are CH; A-(R1)o is ~(R,)n , where each R1 is selected from the group consisting ofH, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, ~CF3 t--{}-cF3 K>- ' , and . 5 wo 2021/222017 PCT/US2021/028836 -17- In a yet still further aspect, in the compounds of formulas (I), (II) and/or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2, or - CD(CH3)CD3; three ofX1, X2, X3, and X4 are CH, while one ofX1, X2, X3, and X4 is N; wO A-(R1)n is ~(R,)n , where each R1 is selected from the group consisting ofH,- ~CF3 ~CF3 ~ CH3, -CH2C(CH3)3, -C(CH3)2CF3, , , and , In one aspect, in the compounds of formulas (I), (II) and/or (III), R2 is isopropyl; X1, X2, X3, and X4 are CH; A-(R1)n is ~,S~ ~"(R1)n , , where each R1 IS selected from the ~CF3 group consisting ofH, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, 10 In another aspect, in the compounds of formulas (I), (II) and/or (III), R2 is 15 isopropyl; three ofX1, X2, X3, and X4 are CH, while one ofX1, X2, X3, and X4 is N; AwS ~(R,), , where each Rt is selected from the group consisting ofH, -CH3,- ~CF3 ~ , and , In an aspect, in the compounds offormulas (I), (II) and/or (Til), R2 is "i: ; Xt, X2, X3, and X4 are CH; A-(R1)n is rs~ ~"(R1)n , , where each R1 IS selected from the ~CF3 group consisting ofH, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, ~CF3 ~ , and , wo 2021/222017 PCT/US2021/028836 -18- In a further aspect, in the compounds of formulas (I), (II) and/or (III), R2 is "1:. ; three ofX1, Xl, X1, and X1 are CH, while one ofX1, X2, x,, and X1 is N; A-(R1)o wS IS ~(R,), , where each R, is selected from the group consisting ofH, -CH,,- ~CF3 ~CF3 ~ CH2C(CH3)3, -C(CH3)2CF3, , , and , 5 In a further aspect, in the compounds of formulas (I), (II) and/or (III), R2 is - CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2, orwS CD(CH1)CD1, X1, X2, X1, and X1 are CH; A-(R1)o is ~(R,), , where each R1 is selected from the group consisting ofH, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, 10 In a yet still further aspect, in the compounds of formulas (I), (II) and/or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2, orCD( CH3)CD3; three ofX1, X2, X3, and X4 are CH, while one ofX1, X2, X3, and X4 is N; wS A-(R1)n is ~(R,), , where each R1 is selected from the group consisting ofH,- ~CF3 ~CF3 ~ CH3, -CH2C(CH3)3, -C(CH3)2CF3, , , and , 15 In one aspect, in the compounds of formulas (I), (II) and/or (III), R2 is isopropyl; CH3 I X1, X2, X3, and X4 are CH; A-(R1)n is ~~NdR1 ore.{ , where R1 is selected 5 10 wo 2021/222017 PCT/US2021/028836 -19- t---0-cF3 from the group consisting ofH, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, In another aspect, in the compounds of formulas (I), (II) and/or (III), R2 is isopropyl; three ofX1, X2, X3, and X4 are CH, while one ofX1, X2, X3, and X4 is N; A- , where R1 is selected from the group consisting of In an aspect, in the compounds offormulas (I), (II) and/or (Til), R2 is "2( ; X1, CH3 I X2, X3, and X4 are CH; A-(R1)n is ~;N;;-R1 or"{ , where R1 is selected t---0-cF3 from the group consisting ofH, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, In a further aspect, in the compounds of formulas (I), (II) and/or (III), R2 is "2( ; three ofX1, Xl, X1, and X4 are CH, while one ofX1, X2, x,, and X4 is N; A-(R1)o CH3 I ~;N;;-R1 or"{ , where R1 is selected from the group consisting of H, - 5 10 15 wo 2021/222017 PCT/US2021/028836 -20- In a further aspect, in the compounds of formulas (I), (II) and/or (III), R2 is - CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2, or- R1 is selected from the group consisting ofH, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, t-Y-cF3 ~CF3 ~ , , and In a yet still further aspect, in the compounds of formulas (I), (II) and/or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2, orCD( CH3)CD3; three ofX1, X2, X3, and X4 are CH, while one ofX1, X2, X3, and X4 is N; CH3 H I A-(R1)n is ~;NQR1 or ~;NQR1 ~ ~ , where R1 is selected from the group consisting and~, In one aspect, in the compounds of formulas (I), (II) and/or (III), R2 is isopropyl; X1, X2, X3, and X4 are CH; A-(R1)n is rn ~(R1)n , , where each R1 IS selected from the t-Y-cF3 group consisting ofH, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, ~CF3 ~ , and , In another aspect, in the compounds of formulas (I), (II) and/or (III), R2 is isopropyl; three ofX1, X2, X3, and X4 are CH, while one ofX1, X2, X3, and X4 is N; A5 10 15 wo 2021/222017 PCT/US2021/028836 -21- ~~ (R1)n , where each R1 is selected from the group consisting ofH, -CH3, ~CF3 f----0---- , and . In an aspect, in the compounds offormulas (I), (II) and/or (Til), R2 is '){, ; X1, ~ X2, X3, and X4 are CH; A-(R1)n is ~(R1)n . , where each R1 IS selected from the ~CF3 group consisting ofH, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, ~CF3 f----0---- , and . In a further aspect, in the compounds of formulas (I), (II) and/or (III), R2 is '){, ; three ofX1, Xl, X1, and X4 are CH, while one ofX1, X2, x,, and X4 is N; A-(R1)o ~~ (R1IS )n , where each R1 is selected from the group consisting ofH, -CH3,- ~CF3 ~CFa f----O---- CH2C(CH3)3, -C(CH3)2CF3, , , and . In a further aspect, in the compounds of formulas (I), (II) and/or (III), R2 is - CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2, or- ~ CD(CH3)CD3; X1, X2, X3, and X4 are CH; A-(R1)n is ~ (R1)n , where each R1 is selected from the group consisting ofH, -CH3, -CH2C(CH3)3, -C(CH3)2CF3, ~CF3 ~CFa f----0---- , , and . 5 10 15 wo 2021/222017 PCT/US2021/028836 -22- In a yet still further aspect, in the compounds of formulas (I), (II) and/or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2, orCD( CH3)CD3; three ofX1, X2, X3, and X4 are CH, while one ofX1, X2, X3, and X4 is N; rn A-(R1)n is ~(R1 )n , w h ere each R1 I0 S se1 e cted fr om t h e group cons10 st0m g o fH , - In another aspect, in the compounds of formulas (I), (II) and/or (III), R2 is ~-~yR1 isopropyl; X1, X2, X3, and X4 are CH; A-(R1)n is ~ where R1 is halogen, ~ , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3,- ~~~). C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, , or CF3. In an aspect, in the compounds of formulas (I), (II) and/or (III), R2 is isopropyl; three ofX1, X2, X3, and X4 are CH, while one ofX1, X2, X3, and X4 is N; A-(R1)n is N ~--yR1 ~ where R1 is halogen, ~ , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, , or CF3. 5 10 15 wo 2021/222017 PCT/US2021/028836 -23- In an aspect, in the compounds offormulas (I), (II) and/or (Til), fu is '){. ; x,, ~-~yR1 X2, X3, and X4 are CH; A-(R1)n is ~ , where R1 is halogen, ~ , - CH2C(CH3 )3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3 )3, -C(CH3 )2CF 3, f /~~~--' C(CH3)2CH2CF3, -C(CH3)3, , or CF3. In a further aspect, in the compounds of formulas (I), (II) and/or (III), R2 is '){. ; three ofX1, X,, x, and X4 are CH, while one ofX1, x,, x,, and X4 is N; A-(R1)o N . ~:_yR1 IS~ ,. 1\., l-/-.!' ! , where R1 is halogen, ~ , -CH2C(CH3)3, 2-chloro-4- , or CF3. In a further aspect, in the compounds of formulas (I), (II) and/or (III), R2 is - CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2, or- N ~~yR1 ~ , where R1 is halogen, ~ , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3,- wo 2021/222017 -24- ~ /'\, ~f· ----r~·--· C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, , or CF3. PCT/US2021/028836 In a yet still further aspect, in the compounds of formulas (I), (II) and/or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2, or- 5 CD(CH3)CD3; three ofX1, X2, X3, and X4 are CH, while one ofX1, X2, X3, and X4 is N; N q~yR1 r , A-(R1)n is where R1 is halogen, f----0< , -CH2C(CH3)3, 2-chloro-4- \7 ~~---··~ fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , or CF3. 10 In another aspect, in the compounds of formulas (I), (II) and/or (III), R2 is q·~yR1 . . rhalogen Isopropyl; X1, X2, X3, and X4 are CH; A-(R1)n IS where R1 is halogen, f----0< , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3,- { ,". t-{-~ C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, , or CF3. 15 In an aspect, in the compounds of formulas (I), (II) and/or (III), R2 is isopropyl; three ofX1, X2, X3, and X4 are CH, while one ofX1, X2, X3, and X4 is N; A-(R1)n is wo 2021/222017 PCT/US2021/028836 -25- ~-~yR1 rhalogen 0 where R1IS halogen, ~ , -CHzC(CH3)3, 2-chloro-4- fluorophenyl, 2,4-dichlorophenyl, -CHzC(CH3)3, -C(CH3)zCF3, l~-:Z , or CF3. 5 In an aspect, in the compounds offormulas (I), (II) and/or (Til), R2 is '){, ; X1, ~-~yR1 0 rhalogen 0 ~ Xz, X3, and X4 are CH; A-(R1)n IS , where R1IS halogen, , - CHzC(CH3 )3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CHzC(CH3 )3, -C(CH3 )zCF 3, ,("v ft..~ ,.,. .... ,~,~ .... ··· < t\. ~kf-.), C(CH3)zCHzCF3, -C(CH3)3, , or CF3. 10 In a further aspect, in the compounds of formulas (I), (II) and/or (III), Rz is '){, ; three ofX1, Xl, X1, and X4 are CH, while one ofX1, X2, x,, and X4 is N; A-(R1)o ~~yR1 0 r halogen h R 0 h l IS , w ere 1 IS a ogen, ~ , -CHzC(CH3)3, 2-chloro-4- \7 /~0-~ fluorophenyl, 2,4-dichlorophenyl, -CHzC(CH3)3, -C(CH3)zCF3, ... ~~'~<.:;) 5 wo 2021/222017 PCT/US2021/028836 -26- , or CF3. In a further aspect, in the compounds of formulas (I), (II) and/or (III), R2 is - CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2, or- ~~yR1 r halogen h R . , w ere 1IS halogen, ~ , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl,- f /~~~-"'""'' -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, , or CF3. In a yet still further aspect, in the compounds of formulas (I), (II) and/or (III), R2 10 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2, orCD( CH3)CD3; three ofX1, X2, X3, and X4 are CH, while one ofX1, X2, X3, and X4 is N; q~yR1 A -(R 1) n I.S r halogen , w h ere R 1 I.S h a l ogen, ~ , -CH2C(CH3)3, 2-chloro-4- fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, 15 , or CF3. 5 10 wo 2021/222017 PCT/US2021/028836 -27- In another aspect, in the compounds of formulas (I), (II) and/or (III), R2 is N'o isopropyl; X1, X2, X3, and X4 are CH; A-(R1)o is p(R,), where at least one R1 is halogen, ~ , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl,- { /'\ r-"t_-C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, , or CF3. In an aspect, in the compounds of formulas (I), (II) and/or (III), R2 is isopropyl; three ofX1, X2, X3, and X4 are CH, while one ofX1, X2, X3, and X4 is N; A-(R1)n is ~,0~ ~"(R1)n . where at least one R1 IS halogen, ~ , -CH2C(CH3)3, 2-chloro-4- ~7 (~'·,·-., fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, l-P ' ! , or CF3. In an aspect, in the compounds offormulas (I), (II) and/or (Til), R2 is "2( ; X1, . ~(Rtlo X2, X3, and X4 are CH; A-(R1)n IS , where at least one R1 is halogen, ~ , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3,- 5 wo 2021/222017 PCT/US2021/028836 -28- ~ /'\, ~f· ----r~·--· C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, , or CF3. In a further aspect, in the compounds of formulas (I), (II) and/or (III), R2 is ~ ; three ofX1, X,, x, and X4 are CH, while one ofX1, x,, x,, and X4 is N; A-(R1)o ~~0~ . ~"(R1)n . IS , where at least one R1 IS halogen, t-O< , -CH2C(CH3 )3, 2-chloro- \7 /-......__~/"""·-,_ 4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3 )3, -C(CH3 )2CF 3, ~- '"· l-r-~ C(CH3)3, , or CF3. In a further aspect, in the compounds of formulas (I), (II) and/or (III), R2 is - 10 CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2, or- ~~0~ ~"(R1)n , where at least one R1 is halogen, t-O< , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl,- .. l"\, l'--(-..:;,. -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, , or CF3. 15 In a yet still further aspect, in the compounds of formulas (I), (II) and/or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2, or5 10 wo 2021/222017 PCT/US2021/028836 -29- CD(CH3)CD3; three ofX1, X2, X3, and X4 are CH, while one ofX1, X2, X3, and X4 is N; wO A-(Rt)" is p(R,), , where at least one Rt is halogen, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3 )3, -C(CH3 )2CF 3, i h. f~~-~ C(CH3)3, . , or CF3. In one aspect, in the compounds of formulas (I), (II) and/or (III), R2 is isopropyl; ~,S~ X1, X2, X3, and X4 are CH; A-(R1)n is ~"(R1)n . , where at least one R1 IS halogen, ~ , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3,- N.'\~ ~ ! -- C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, , or CF3. In another aspect, in the compounds of formulas (I), (II) and/or (III), R2 is isopropyl; three ofX1, X2, X3, and X4 are CH, while one ofX1, X2, X3, and X4 is N; AwS (Rt)" is p(R,)" , where at least one Rt is halogen, \.! .. ).( l~./ '·',., chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, · , wo 2021/222017 PCT/US2021/028836 -30- ti' !_l") , C(CH3)3, . , or CF3. In an aspect, in the compounds offormulas (I), (II) and/or (Til), R2 is "£ ; X1, X2, X3, and X4 are CH; A-(R1)n is rs~ ~"(R1)n . , where at least one R1 IS halogen, 5 ~ , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3,- { ,r-., r-f~ C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, , or CF3. In a further aspect, in the compounds of formulas (I), (II) and/or (III), R2 is "£ ; three ofX1, X,, x, and X4 are CH, while one ofX1, x,, x,, and X4 is N; A-(R1)o 10 ~,S~ . ~"(R1)n . IS , where at least one R1 IS halogen, ~ , -CH2C(CH3 )3, 2-chloro- 4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3 )3, -C(CH3 )2CF 3, f .1'' I ' r--r---~ C(CH3)3, , or CF3. In a further aspect, in the compounds of formulas (I), (II) and/or (III), R2 is - 15 CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2, orwo 2021/222017 PCT/US2021/028836 -31- ~,S~ ~'(R1}n , where at least one R1 is halogen, ~ , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl,- , or CF3. 5 In a yet still further aspect, in the compounds of formulas (I), (II) and/or (III), R2 10 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2, orCD( CH3)CD3; three ofX1, X2, X3, and X4 are CH, while one ofX1, X2, X3, and X4 is N; wS A-(Rt)" is ;u(R,)n , where at least one Rt is halogen, \:/ /-..-../-~ 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3 )3, -C(CH3 )2CF 3, f li-'f--~ C(CH3)3, , or CF3. In another aspect, in the compounds of formulas (I), (II) and/or (III), R2 is CH3 H I ~~Ng--R1 ~~Ng--R1 isopropyl; X1, X2, X3, and X4 are CH; A-(R1)nis ~ or~ where R1 is halogen, ~ , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl,- 5 10 wo 2021/222017 PCT/US2021/028836 -32- t_ /''..., ~f- ----r'--· -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, , or CF3. In an aspect, in the compounds of formulas (I), (II) and/or (III), R2 is isopropyl; three ofX1, X2, X3, and X4 are CH, while one ofX1, X2, X3, and X4 is N; A-(R1)n is CH3 H I ~;N~~R1 ~;N~~R1 ~ or~ where R1 is halogen, t-O< , -CH2C(CH3)3, 2-chloro-4- \7 ~~---··~ fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , or CF3. In an aspect, in the compounds offormulas (I), (II) and/or (Til), fu is ~ ; x,, CH3 H I ~;N~~R1 ~;N~~R1 X2, X3, and X4 are CH; A-(R1)n is ~ or~ , where R1 is halogen, t-O< , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3,- 5 10 wo 2021/222017 PCT/US2021/028836 -33- In a further aspect, in the compounds of formulas (I), (II) and/or (III), R2 is "1:. ; three ofX1, Xl, X1, and X4 are CH, while one ofX1, X2, x,, and X4 is N; A-(R1)o CH3 H I ~\N/rR1 ~\N/rR1 IS ~ or~ , where R1 is halogen, chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3 )3, -C(CH3 )2CF 3, ~-5"Z, i /t~--~ C(CH3)3, . , or CF3. In a further aspect, in the compounds of formulas (I), (II) and/or (III), R2 is - CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2, or- R1 is halogen, ~ , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl,- ft .-11/ ''-_..,. ~- -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, . , or CF3. In a yet still further aspect, in the compounds of formulas (I), (II) and/or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2, or- 15 CD(CH3)CD3; three ofX1, X2, X3, and X4 are CH, while one ofX1, X2, X3, and X4 is N; wo 2021/222017 PCT/US2021/028836 -34- CH3 H I A-(R1)n is ~~NrR1 ~~NrR1 ~ or~ , where R1 is halogen, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3 )3, -C(CH3 )2CF 3, f .1'' I ' r--r---~ C(CH3)3, , or CF3. \/ l--../·-~ 5 In one aspect, in the compounds of formulas (I), (II) and/or (III), R2 is isopropyl; X1, X2, X3, and X4 are CH; A-(R1)n is rn ~(R1)n . , where each R1IS halogen, ~ , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3,- ~--+. '"').. ~( C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, , or CF3. 10 In another aspect, in the compounds of formulas (I), (II) and/or (III), R2 is isopropyl; three ofX1, X2, X3, and X4 are CH, while one ofX1, X2, X3, and X4 is N; Arn (R1) n I.S ~(R1 )n , w h ere eac hR1 I.S h a1 o gen, ~ , -CH2C(CH3 )3, 2-chloro- \-....... , /"~ .> l . ....,_. .. / ··-.,, 4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, , wo 2021/222017 PCT/US2021/028836 -35- ti' !_l") , C(CH3)3, . , or CF3. In an aspect, in the compounds offormulas (I), (II) and/or (Til), R2 is "£ ; X1, X2, X3, and X4 are CH; A-(R1)n is rn ~(R1)n . , where each R1 IS halogen, 5 t---<>( , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3,- < !'· f-_rl_'). ~ C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, , or CF3. In a further aspect, in the compounds of formulas (I), (II) and/or (III), R2 is "£ ; three ofX1, Xl, X1, and X4 are CH, while one ofX1, X2, x,, and X4 is N; A-(R1)o 10 rn . ~(R1 )n h hR . h 1 IS , w ere eac 1 IS a ogen, t---0< , -CH2C(CH3)3, 2-chloro-4- l \7 ~--/~.> l -... __ ..... -~ ~- fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3)3, -C(CH3)2CF3, · , , or CF3. In a further aspect, in the compounds of formulas (I), (II) and/or (III), R2 is - 15 CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2, or5 10 wo 2021/222017 PCT/US2021/028836 -36- rn ~(R1)n . , where each R11s halogen, ~ , -CH2C(CH3)3, 2-chloro-4-fluorophenyl, 2,4-dichlorophenyl,- c fi-i-·~' -C(CH3)2CF2CH3, -C(CH3)2CH2CF3, -C(CH3)3, , or CF3. In a yet still further aspect, in the compounds of formulas (I), (II) and/or (III), R2 is -CH(CH3)CF2D, -CH(CD3)2, -CH(CF3)CD3, -CH(CH3)CDF2, -CD(CD3)2, orCD( CH3)CD3; three ofX1, X2, X3, and X4 are CH, while one ofX1, X2, X3, and X4 is N; vO A-(R1)n is ~ (R1)n , where each R1 is halogen, rI-· ··"-.,..._/S ?~-.~ . ... chloro-4-fluorophenyl, 2,4-dichlorophenyl, -CH2C(CH3 )3, -C(CH3 )2CF 3, ti' !_l") , C(CH3)3, . , or CF3. Whenever a variable is defined as "each," for example, "each R1 is ... " it is understood that the definition of the variable at each occurrence is independently selected from the groups contained in the definition. Thus, for example, if a phenyl is substituted 15 with four R1 groups, the identity of each R1 group is independently selected from the groups listed in the definition ofR1. Accordingly, all four R1 groups may be the same or they may all be different or some of the groups may be the same, while others are different. Specific enantiomers may be prepared beginning with chiral reagents or by stereo- 20 selective or stereo-specific synthetic techniques. Alternatively, single enantiomers may wo 2021/222017 PCT/US2021/028836 -37- be isolated from mixtures of different chiral forms by standard chiral chromatographic or crystallization techniques at any convenient point in the synthesis of compounds of formula (I), formula (II), and formula (III). All individual enantiomers, as well as mixtures of the enantiomers of the compounds of formula (II) and formula (III) including 5 racemates are intended to be included herein. Specific examples of the compounds of formula (I) including the forms of formula (II) and formula (III) are shown in the Examples below. A subset of useful molecules from the Examples is shown in Table A Table A Example# Structure CH3 H H2N 0 I O N~N ~ _h. 1 (Isomer 1) H2N ~, N-N ~ ~0~ 15 (Isomer 1) H2N N H IN ~a;YcF, 17 (Isomer 1) H2N N H IN ¢,CF3 0 0 I 31 (Isomer 1) NH2 0 N H2N - N :::;- H I. :-. A ~N-N N wo 2021/222017 PCT/US2021/028836 -38- 33 (Isomer 1) 35 (Isomer 1) 0 o;YH2N NH2 0 ::;;..-- r; ~ N IN-~ H - 45 (Isomer 1) 52 (Isomer 2) 64 (Isomer 2) 0 ¢;' H2N NH2 0 - N :::;..- H \N-~ \ !J N 66 (Isomer 2) 0 t H2N NH2 0 - N :::;..- H \N-~ \ /; N wo 2021/222017 -39- 68 (Isomer 2) 70 (Isomer 2) 76 (Isomer 2) 80 (Isomer 2) 81 (Isomer 1) N H PCT/US2021/028836 ¢CF3 0 I N N H wo 2021/222017 -40- 84 (Isomer 2) 90 (Isomer 2) 94 (Isomer 2) 98 (Isomer 1) 0 36c (Isomer 1) 36g (Isomer 1) H N PCT/US2021/028836 Cl p--