US20160215006A1

US20160215006A1 - Peptidomimetic inhibitors of psma

Info

Publication number: US20160215006A1
Application number: US15/088,390
Authority: US
Inventors: Clifford E. Berkman; Henry F. VanBrocklin
Original assignee: University of California; Washington State University WSU
Current assignee: University of California; Washington State University WSU
Priority date: 2010-11-12
Filing date: 2016-04-01
Publication date: 2016-07-28
Also published as: WO2012064914A3; US9328129B2; US20140010758A1; WO2012064914A2

Abstract

Compounds of the formulae, (I), wherein each variable is as defined herein are provided which are useful in (i) diagnostic methods for detecting and/or identifying cells presenting PSMA; (2) compositions comprising a compound of the invention together with a pharmaceutically acceptable carrier, excipient, and/or diluent; (3) methods for inhibiting or treating prostrate cancer; and (4) methods for blocking or destabilizing neovasculature of a tumor.

Description

STATEMENT OF GOVERNMENT INTEREST

This application was supported by Grant No. 1R21CA135463-01, 1R21CA122126-01 and 1R01CA140617-01A2 awarded by National Institutes of Health and the National Cancer Institute. The U.S. government has certain rights in the invention.

BACKGROUND OF THE INVENTION

1. Field of the Invention
The present invention relates to small molecules having high affinity and specificity to prostrate-specific membrane antigen (PSMA) and methods of using them for diagnostic and therapeutic purposes.
2. Summary of the Related Art
Prostate-specific membrane antigen (PSMA) is uniquely overexpressed on the surface of prostate cancer cells as well as in the neovasculature of a variety of solid tumors. As a result, PSMA has attracted attention as a clinical biomarker for detection and management of prostate cancer. Generally, these approaches utilize an antibody specifically targeted at PSMA to direct imaging or therapeutic agents. For example, ProstaScint (Cytogen, Philadelphia, Pa.), which has been approved by the FDA for the detection and imaging of prostate cancer, utilizes an antibody to deliver a chelated radioisotope (Indium-111). However, it is now recognized that the ProstaScint technology is limited to the detection of dead cells and therefore its clinical relevance is questionable.
The success of cancer diagnosis and therapy using antibodies is limited by challenges such as slow elimination of these biomolecules from the blood and poor vascular permeability. In addition, large antibodies bound to cell-surface targets present a barrier for subsequent binding of additional antibodies at neighboring cell-surface sites resulting in a decreased cell-surface labeling.
In addition to serving as a cell-surface target for antibodies delivering diagnostic or therapeutic agents, a largely overlooked and unique property of PSMA is its enzymatic activity. That is, PSMA is capable of recognizing and processing molecules as small as dipeptides. Despite the existence of this property, it has been largely unexplored in terms of the development of novel diagnostic and therapeutic strategies. There are a few recent examples in the literature that have described results in detecting prostate cancer cells using labeled small-molecule inhibitors of PSMA.
Certain phosphoramidate PSMA inhibitors have been described in U.S. Pat. No. 7,696,185 to Berkman.

SUMMARY OF THE INVENTION

The present invention comprises compounds that bind to the prostate-specific membrane antigen (PSMA) with high affinity and specificity.
In one aspect, the present disclosure comprises compounds of one of the formulae,
wherein each variable is as defined herein.
In another aspect, the present invention comprises compositions comprising a compound of the invention together with a pharmaceutically acceptable carrier, excipient, and/or diluent.
In another aspect, the present invention comprises diagnostic methods for detecting and/or identifying cells presenting PSMA comprising contacting (or causing to be contacted) a cell suspected of presenting PSMA with a compound of the invention.
In another aspect, the present invention comprises compositions comprising a compound of the invention together with a pharmaceutically acceptable carrier, excipient, and/or diluent.
In another aspect, the present invention comprises methods for inhibiting or treating prostrate cancer comprising administering to a patient having prostrate cancer a therapeutically effective amount of a compound of the invention linked to a prostrate cancer therapeutic agent (or a composition thereof).
In another aspect, the present invention comprises methods for blocking or destabilizing neovasculature of a tumor, comprising administering to a patient having a tumor; or contacting a tumor cell with a therapeutically effective amount of a compound or composition of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows uptake of DTPA-SCN-CTT-54 labeled with pertechnetate (^99mTcO₄) reduced with SnCl₂by LNCaP (PSMA+) and PC3 (PSMA−) cells.

FIG. 2 shows uptake DTPA-SCN-CTT-54 labeled with ^99mTc(CO)₃by LNCaP (PSMA+) and PC3 (PSMA−) cells.

FIG. 3 shows biodistribution of the ^99mTc-labeled probe in a LNCaP PSMA+ tumor xenograft model 4 hours following tail-vein probe injection.

DETAILED DESCRIPTION OF THE INVENTION

In embodiment (1) of the first aspect, the invention comprises the compound of formula (I),
and pharmaceutically acceptable salts thereof wherein

X and Y are independently —O— or —N(R)—, wherein each R is independently hydrogen, —C₁-C₇alkyl, —C₁-C₇alkylaryl, —C₁-C₇alkylheteroaryl, or a protecting group;
m is 1, 2, 3, 4, 5, or 6;
n is 1, 2, 3, 4, 5, or 6;
R¹and R²are each independently —C(O)OR³, —C(O)N(R³)₂, —P(O)(OR³)₂, —OP(O)(OR³)₂, —S(O)₂R³, —S(O)₂OR³, —S(O)₂N(R³)₂, or tetrazolyl;
each R³is independently hydrogen, —C₁-C₇alkyl, —C₁-C₇alkylaryl, —C₁-C₇alkylbeteroaryl, or a protecting group;
R⁴is hydrogen, —C(O)OR³, —C(O)N(R³)₂, —P(O)(OR³)₂, —OP(O)(OR³)₂, —S(O)₂R³, —S(O)₂OR³, —S(O)₂N(R³)₂, or tetrazolyl;
R⁵is hydrogen, —C₁-C₇alkyl, —C₁-C₇alkylaryl, —C₁-C₇alkylheteroaryl, or a protecting group;
each R⁶is independently hydrogen, C₁-C₄alkyl, or fluoro;
M is —O—, —S—, —N(R³¹)—, or —CH₂—, wherein R³¹is hydrogen, —C₁-C₇alkyl, —C₁-C₇alkylaryl, —C₁-C₇alkylheteroaryl, or a protecting group;
R⁷is -L-R¹⁰, wherein
- L is —C(O)—, -(Pep)-C(O)—, —C(O)N(H)—, —O(O)O—, —C(S)N(H)—, or —C(S)O—, wherein
- Pep is a polypeptide of 1-20 amino acids; and
- R¹⁰is -aryl-R⁹, -heteroaryl-R⁹, —C₁-C₇alkyl-aryl-R⁹, —C₁-C₇alkyl-heteroaryl -R⁹, —C₁-C₇alkyl-R⁸, -aryl-C₁-C₇alkyl-R⁸, or -heteroaryl-C₁-C₇alkyl-R⁸, wherein
  - the aryl, heteroaryl, -alkyl-aryl, -aryl-alkyl, -alkyl-heteroaryl, and -heteroaryl-alkyl groups are optionally and independently substituted with one, two, or three groups which are each independently —O(O)R¹¹, —CO(O)R¹², —C(O)N(R¹²)₂, wherein
    - each R¹¹is independently hydrogen, —C₁-C₇alkyl, —C₁-C₇alkylaryl, or —C₁-C₇alkylheteroaryl; and
    - each R¹²is independently R¹¹or a protecting group;
- and
- R⁸is —C(H)(COOR³)N(R¹⁵)-L¹-(C₁-C₇)alkyl-R⁹,
  - —O(H)(COOR³)N(R ¹⁵)-L¹-aryl-R⁹,
  - —C(H)(COOR³)N(R¹⁵)-L¹-heteroaryl-R⁹,
  - —C(H)(COOR³)N(R¹⁵)-L¹-aryl(C₁-C₇)alkyl-R⁹,
  - —O(H)(COOR³)N(R¹⁵)-L¹-heteroaryl(C₁-C₇)alkyl-R⁹,
  - —C(H)(COOR³)N(R¹⁵)-L¹-G-CH₂CH₂—R⁹,
  - —C(H)(COOR³)N(R¹⁵)-L¹-(C₁-C₇)alkyl-O—(C₁-C₇)alkyl-R⁹,
  - or R⁹,
  - wherein
  - R¹⁵is hydrogen, —C₁-C₇alkyl, alkylaryl, —C₁-C₇alkylheteroaryl, or a protecting group;
  - L¹is —C(O)—, —C(O)N(H)—, —C(O)O—, —C(S)N(H)—, or —C(S)O—; and
  - the aryl, heteroaryl, arylalkyl, and heteroarylalkyl groups are optionally substituted with one, two, or three groups which are each independently halomethyl dihalomethyl, trihalomethyl, —C(O)R⁸¹, —C(O)N(R⁸²)₂, -, wherein
    - each R⁸¹is independently hydrogen, —C₁-C₇alkyl, —C₁-C₇alkylaryl, or —C₁-C₇alkylheteroaryl; and
    - each R⁸²is independently R⁸¹or a protecting group;
  - G is —(CH₂CH₂O)_q—, wherein q is an integer from 1 to 200 (e.g., q is 100-200, 150-200, 1-100, 1-50, 1-10, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10);
R⁹is (1) —N₃, —C≡CH, —ONH₂, —C(O)N(H)NH₂, or —N(H)NH₂;
- - - (ii) a detectable label, a cytotoxic group, or biotin;
    - (iii) a pendant group comprising either a detectable label, a cytotoxic group, or biotin; or
    - (iv) a pendant group bonded to a solid support.

The invention further comprises subgenera of embodiment (1) of the first aspect in which the substituents are selected as any and all combinations of R, R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, R¹¹, R¹², R¹⁵, R³¹, R⁸¹, R⁸², L, L¹, M, X, Y, in, and n, as defined herein, including without limitation, the following:
R¹in formula (I) is one of the following groups (1a)-(1l):

- (1a) —C(O)OR³or —C(O)N(R³)₂.
- (1b) —C(O)OR³.
- (1c) —C(O)OR³⁴, wherein R³⁴is hydrogen, —C₁-C₇alkyl, —C₁-C₇alkylaryl, or a protecting group.
- (1d) —C(O)OR³⁴, wherein R³⁴is hydrogen or —C₁-C₇alkyl aryl.
- (1e) —C(O)OR³⁴, wherein R³⁴is hydrogen or benzyl.
- (1 f) —C(O)OR³⁴, wherein R³⁴is benzyl.
- (1g) —C(O)OR³⁴, wherein R³⁴is hydrogen or a protecting group.
- (1h) —C(O)OR³⁴, wherein R³⁴is a protecting group.
- (1i) —C(O)OH.
- (1j) —P(O)(OR³)₂or —OP(O)(OR³)₂.
- (1k) —S(O)₂R³, —S(O)₂OR³or —S(O)₂N(R³)₂.
- (1l) tetrazolyl.

R²in formula (1) is one of the following groups (2a)-(2j):

- (2a) —C(O)OR³or —C(O)N(R³)₂.
- (2b) —C(O)OR³.
- (2c) —C(O)OR³²wherein R³²is hydrogen, —C₁-C₇alkyl, —C₁-C₇alkylaryl, or a protecting group.
- (2d) —C(O)OR³²wherein R³²is hydrogen or —C₁-C₇alkylaryl.
- (2e) —C(O)OR³²wherein R³²is hydrogen or benzyl.
- (2f) —C(O)OR³²wherein R³²is benzyl.
- (2g) —C(O)OH.
- (2h) —P(O)(OR³)₂or —OP(O)(OR³)₂.
- (2i) —S(O)₂R³; —S(O)₂OR³or —S(O)₂N(R³)₂.
- (2j) tetrazolyl.

R⁴in formula (I) is one of the following groups (3a)-(3k):

- (3a) hydrogen, —C(O)OR³, or —C(O)N(R³)₂.
- (3b) hydrogen or —C(O)OR³.
- (3c) —C(O)OR³³wherein R³³is hydrogen, —C₁-C₇alkyl, —C₁-C₇alkylaryl, or a protecting group.
- (3d) —C(O)OR³³wherein R³³is hydrogen or —C₁-C₇alkylaryl.
- (3e) —C(O)OR³³wherein R³³is hydrogen or benzyl.
- (3f) —C(O)OR³³wherein R³³is benzyl.
- (3g) —C(O)OH.
- (3h) —P(O)(OR³)₂or —OP(O)(OR³)₂
- (3i) —S(O)₂R³, —S(O)₂OR³or —S(O)₂N(R³)₂.
- (3j) tetrazolyl.
- (3k) hydrogen.

R⁷in formula (I) is one of the following groups (4a)-(4w):

- (4a) —C(O)R¹⁰.
- (4h) (Pep)-C(O)R¹⁰.
- (4c) —C(O)C₁-C₇alkyl-R⁸.
- (4d) —C(O)C₁-C₇alkyl-R⁸, wherein R⁸is —C(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-R⁹, —C(H)(COOR³)N(H)-L¹-heteroaryl-R⁹, —C(H)(COOR³)N(H)-L¹-G-CH₂CH₂—R⁹, —C(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-O—(C₁-C₇)alkyl-R⁹, or —R⁹.
- (4e) —C(O)C₁-C₇alkyl-R⁸, wherein R⁸is —C(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-R⁹, —C(H)(COOR³)N(H)-L¹-G-CH₂CH₂—R⁹, —C(H)(COOR³)N(H)-L ¹-(C ₁-C₇)alkyl-O—(C₁-C₇)alkyl-R⁹, or R⁹.
- (4f) —C(O)C₁-C₇alkylC(H)(COOR³)N(H)-L¹-(C ₁-C₇)alkyl-R⁹.
- (4g) —C(O)C₁-C₇alkylC(H)(COOR³)N(H)-L¹-heteroaryl-R⁹,
- (4h) —C(O)C₁-C₇alkylC(H)(COOR³)N(H)-L¹-pyridyl-R⁹,
- (4i) —C(O)C₁-C₇alkylC(H)(COOR³)N(H)-L¹-aryl-R⁹,
- (4j) —C(O)C ₁-C₇alkylC(H)(COOR³)N(H)-L ¹-phenyl-R⁹,
- (4k) —C(O)C₁-C₇alkyl-C(H)(COOR³)N(H)-L¹-G-CH₂—R⁹.
- (4l) —C(O)C₁-C₇alkyl-C(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-O—(C₁-C₇)alkyl-R⁹.
- (4m) (Pep)-C(O)C₁-C₇alkyl-R⁸, wherein R⁸is —C(H)(COOR³)N(H)-L¹-(C₁-C₇)allcyl-R⁹, —C(H)(COOR³)N(H)-L¹-heteroaryl-R⁹,—C(H)(COOR³)N(H)-L¹-G-CH₂CH₂—R⁹, —C(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-O—(C₁-C₇)alkyl-R⁹, or R⁹.
- (4n) (Pep)-C(O)C₁-C₇alkyl-R⁸, wherein R⁸is C(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-R⁹, —C(H)(COOR³)N(H)-L¹-G-CH₂CH₂—R⁹,—C(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-O—(C₁-C₇)alkyl-R⁹, or R⁹.
- (4o) (Pep)-C(O)—C₁-C₇alkylC(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-R⁹.
- (4p) (Pep)-C(O)—C₁-C₇alkyl-C(H)(COOR³)N(H)-L¹-G-CH₂CH₂—R⁹.
- (4q) (Pep)-C(O)C₁-C₇alkyl-C(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-O-(C₁-C₇)alkyl-R⁹.
- (4r) (Pep)-C(O)C₁-C₇alkyl-R⁸.
- (4s) any one of groups (4d)-(4o), wherein L¹is —C(O)—.
- (4t) any one of groups (4d)-(4o), wherein L¹is —C(O)—, —C(O)N(H)—, —C(O)O—, —C(S)N(H)—, or —C(S)O—.
- (4u) any one of groups (4d)-(4o), wherein L¹is —C(O)N(H)—, —C(O)O—, —C(S)N(H)—, or —C(S)O—.
- (4v) any one of groups (4d)-(4o), wherein L¹is —C(O)N(H)— or —C(S)N(H)—.
- (4w) any one of groups (4d)-(4o), wherein L¹is —C(O)N(H)—.

R⁸in formula (I) is one of the following groups (5a)-(5o):

- (5a) C(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-R⁹, —C(H)(COOR³)N(H)-L¹-heteroaryl-R⁹, —C(H)(COOR³)N(H)-L¹-G-CH₂CH₂—R⁹, —C(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-O—(C₁-C₇)allcyl-R⁹, or —R⁹.
- (5b) —C(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-R⁹, —C(H)(COOR³)N(H)-L¹-G-CH₂OH₂—R⁹, —C(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-O—(C₁-C₇)alkyl-R⁹, or —R⁹.
- (5c) —C(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-R⁹.
- (5d) —C(H)(COOR³)N(H)-L¹-G-CH₂CH₂—R⁹.
- (5e) —C(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-O—(C₁-C₇)alkyl-R⁹.
- (5f) —C(H)(COOR³)N(H)-L¹-heteroaryl-R⁹,
- (5g) —C(H)(COOR³)N(H)-L¹-pyridyl-R⁹,
- (5h) —C(H)(COOR³)N(H)-L¹-aryl-R⁹,
- (5i) —C(H)(COOR³)N(H)-L¹-phenyl-R⁹,
- (5j) —R⁹.
- (5k) any one of groups (5a)-(5g), wherein L¹is —C(O)—.
- (5l) any one of groups (5a)-(5g), wherein L¹is —C(O)—, —C(O)N(H)—, —C(O)O—, —C(S)N(H)—, or —C(S)O—.
- (5m) any one of groups (5a)-(5g), wherein L¹is —C(O)N(H)—, —C(O)O—, —C(S)N(H)—, or —C(S)O—.
- (5n) any one of groups (5a)-(5g), wherein is —C(O)N(H)— or —C(S)N(H)—.
- (5o) any one of groups (5a)-(5g), wherein L¹is —C(O)N(H)—.

L in formula (I) is one of the following groups (5p)-(5u):

- (5p) —C(O)—.
- (5q) -(Pep)-C(O)—.
- (5r) —C(O)—, —C(O)N(H)—, —C(O)O—, —C(S)N(H)—, or —C(S)O—.
- (5s) —C(O)N(H)—, —C(O)O—, —C(S)N(H)—, or —C(S)O—.
- (5t) —C(O)N(H)— or —C(S)N(H)—.
- (5u) —C(O)N(H)—.

L¹in formula (I) is one of the following groups (5v)-(5z):

- (5v) —C(O)—.
- (5w) —C(O)—, —C(O)N(H)—, —C(O)O—, —C(S)N(H)—, or —C(S)O—.
- (5x) —C(O)N(H)—, —C(O)O—, —C(S)N(H)—, or —C(S)O—.
- (5y) —C(O)N(H)— or —C(S)N(H)—.
- (5z) —C(O)N(H)—.

M in formula (I) is one of the following groups (6a)-(6e):

- (6a) —O—, —S—, or —N(R³¹)—.
- (6b) —O—.
- (6c) —S—.
- (6) —N(R³¹)—.
- (6e) —N(H)—.

X and Y in formula (1) are one of the following groups (7a)-(7g):

- (7a) X and Y are each —O—.
- (7b) X is —O— and Y is —N(R)—.
- (7c) Y is —O— and X is —N(R)—.
- (7d) X is —O— and Y is —N(H)—.
- (7e) Y is —O— and X is —N(H)—.
- (7f) X and Y are each —N(R)—.
- (7g) X and Y are each —N(H)—.

m and n in formula (1) are one of the following groups (8a)-(8g):

- (8a) m is 1, 2, 3, 4, 5, or 6 and n is 1, 2, or 3.
- (8b) m is 1, 2, or 3 and n is 1, 2, 3, 4, 5, or 6.
- (8c) in is 1, 2, or 3 and n is 1, 2, or 3.
- (8d) in is 1 or 2 and n is 1 or 2. 1

(8e) in is 1 or 2 and n is 1.

- (8f) m is 1 and n is 1 or 2.
- (8g) m is 1 and n is 1.

R⁵in formula (I) is one of the following groups (8h)-(8l):

- (8h) hydrogen, —C₁-C₇alkyl, —C₁-C₇alkyl aryl, or —C₁-C₇alkylheteroaryl.
- (8i) hydrogen, methyl, ethyl, t-butyl, or benzyl.
- (8j) hydrogen.
- (8k) hydrogen or benzyl.
- (8l) benzyl.

each R⁶in formula (I) is independently one of the following groups (8m)-(8q):

- (8m) methyl or fluoro.
- (8n) hydrogen, methyl, or fluoro.
- (8o) hydrogen or methyl.
- (8p) hydrogen or fluoro.
- (8q) hydrogen.

each of variables R, R¹¹, R¹², R¹⁵, R³¹, R⁸¹, and R⁸²in formula (I) are independently selected from one of the following groups (8r)-(8v):

- (8r) hydrogen, —C₁-C₇alkyl, —C₁-C₇alkylaryl, or —C₁-C₇alkylheteroaryl.
- (8s) hydrogen, —C₂-C₇alkyl, or —C₁-C₇alkylaryl.
- (8t) hydrogen or —C₁-C₇alkyl.
- (8u) hydrogen.
- (8v) —C₁-C₇alkyl.

Particular embodiments of this aspect of the invention include compounds of formula (I) wherein are defined in each of the following rows, wherein each entry is a group number as defined above for formula (I) (e.g., (8e) refers to m is 1-6, in a sub-embodiment m is 1, n is 1):


Embodiment	R¹	R²	R⁴	R⁶	R⁷	X & Y	m & n	M

I-1	1b	2b	3b	8m	4d	7a	8c	6a
I-2	1b	2b	3e	8m	4d	7a	8c	6a
I-3	1b	2b	3k	8m	4d	7a	8c	6a
I-4	1b	2b	3b	8m	4d	7a	8c	6d
I-5	1b	2b	3e	8m	4d	7a	8c	6d
I-6	1b	2b	3k	8m	4d	7a	8c	6d
I-7	1b	2b	3b	8m	4d	7a	8e	6a
I-8	1b	2b	3e	8m	4d	7a	8e	6a
I-9	1b	2b	3k	8m	4d	7a	8e	6a
I-10	1b	2b	3b	8m	4d	7a	8e	6d
I-11	1b	2b	3e	8m	4d	7a	8e	6d
I-12	1b	2b	3k	8m	4d	7a	8e	6d
I-13	1b	2b	3b	8m	4d	7b	8c	6a
I-14	1b	2b	3e	8m	4d	7b	8c	6a
I-15	1b	2b	3k	8m	4d	7b	8c	6a
I-16	1b	2b	3b	8m	4d	7b	8c	6d
I-17	1b	2b	3e	8m	4d	7b	8c	6d
I-18	1b	2b	3k	8m	4d	7b	8c	6d
I-19	1b	2b	3b	8m	4d	7b	8e	6a
I-20	1b	2b	3e	8m	4d	7b	8e	6a
I-21	1b	2b	3k	8m	4d	7b	8e	6a
I-22	1b	2b	3b	8m	4d	7b	8e	6d
I-23	1b	2b	3e	8m	4d	7b	8e	6d
I-24	1b	2b	3k	8m	4d	7b	8e	6d
I-25	1b	2b	3b	8m	4f	7a	8c	6a
I-26	1b	2b	3e	8m	4f	7a	8c	6a
I-27	1b	2b	3k	8m	4f	7a	8c	6a
I-28	1b	2b	3b	8m	4f	7a	8c	6d
I-29	1b	2b	3e	8m	4f	7a	8c	6d
I-30	1b	2b	3k	8m	4f	7a	8c	6d
I-31	1b	2b	3b	8m	4f	7a	8e	6a
I-32	1b	2b	3e	8m	4f	7a	8e	6a
I-33	1b	2b	3k	8m	4f	7a	8e	6a
I-34	1b	2b	3b	8m	4f	7a	8e	6d
I-35	1b	2b	3e	8m	4f	7a	8e	6d
I-36	1b	2b	3k	8m	4f	7a	8e	6d
I-37	1b	2b	3b	8m	4f	7b	8c	6a
I-38	1b	2b	3e	8m	4f	7b	8c	6a
I-39	1b	2b	3k	8m	4f	7b	8c	6a
I-40	1b	2b	3b	8m	4f	7b	8c	6d
I-41	1b	2b	3e	8m	4f	7b	8c	6d
I-42	1b	2b	3k	8m	4f	7b	8c	6d
I-43	1b	2b	3b	8m	4f	7b	8e	6a
I-44	1b	2b	3e	8m	4f	7b	8e	6a
I-45	1b	2b	3k	8m	4f	7b	8e	6a
I-46	1b	2b	3b	8m	4f	7b	8e	6d
I-47	1b	2b	3e	8m	4f	7b	8e	6d
I-48	1b	2b	3k	8m	4f	7b	8e	6d
I-49	1b	2e	3b	8m	4d	7a	8c	6a
I-50	1b	2e	3e	8m	4d	7a	8c	6a
I-51	1b	2e	3k	8m	4d	7a	8c	6a
I-52	1b	2e	3b	8m	4d	7a	8c	6d
I-53	1b	2e	3e	8m	4d	7a	8c	6d
I-54	1b	2e	3k	8m	4d	7a	8c	6d
I-55	1b	2e	3b	8m	4d	7a	8e	6a
I-56	1b	2e	3e	8m	4d	7a	8e	6a
I-57	1b	2e	3k	8m	4d	7a	8e	6a
I-58	1b	2e	3b	8m	4d	7a	8e	6d
I-59	1b	2e	3e	8m	4d	7a	8e	6d
I-60	1b	2e	3k	8m	4d	7a	8e	6d
I-61	1b	2e	3b	8m	4d	7b	8c	6a
I-62	1b	2e	3e	8m	4d	7b	8c	6a
I-63	1b	2e	3k	8m	4d	7b	8c	6a
I-64	1b	2e	3b	8m	4d	7b	8c	6d
I-65	1b	2e	3e	8m	4d	7b	8c	6d
I-66	1b	2e	3k	8m	4d	7b	8c	6d
I-67	1b	2e	3b	8m	4d	7b	8e	6a
I-68	1b	2e	3e	8m	4d	7b	8e	6a
I-69	1b	2e	3k	8m	4d	7b	8e	6a
I-70	1b	2e	3b	8m	4d	7b	8e	6d
I-71	1b	2e	3e	8m	4d	7b	8e	6d
I-72	1b	2e	3k	8m	4d	7b	8e	6d
I-73	1b	2e	3b	8m	4f	7a	8c	6a
I-74	1b	2e	3e	8m	4f	7a	8c	6a
I-75	1b	2e	3k	8m	4f	7a	8c	6a
I-76	1b	2e	3b	8m	4f	7a	8c	6d
I-77	1b	2e	3e	8m	4f	7a	8c	6d
I-78	1b	2e	3k	8m	4f	7a	8c	6d
I-79	1b	2e	3b	8m	4f	7a	8e	6a
I-80	1b	2e	3e	8m	4f	7a	8e	6a
I-81	1b	2e	3k	8m	4f	7a	8e	6a
I-82	1b	2e	3b	8m	4f	7a	8e	6d
I-83	1b	2e	3e	8m	4f	7a	8e	6d
I-84	1b	2e	3k	8m	4f	7a	8e	6d
I-85	1b	2e	3b	8m	4f	7b	8c	6a
I-86	1b	2e	3e	8m	4f	7b	8c	6a
I-87	1b	2e	3k	8m	4f	7b	8c	6a
I-88	1b	2e	3b	8m	4f	7b	8c	6d
I-89	1b	2e	3e	8m	4f	7b	8c	6d
I-90	1b	2e	3k	8m	4f	7b	8c	6d
I-91	1b	2e	3b	8m	4f	7b	8e	6a
I-92	1b	2e	3e	8m	4f	7b	8e	6a
I-93	1b	2e	3k	8m	4f	7b	8e	6a
I-94	1b	2e	3b	8m	4f	7b	8e	6d
I-95	1b	2e	3e	8m	4f	7b	8e	6d
I-96	1b	2e	3k	8m	4f	7b	8e	6d
I-97	1e	2b	3b	8m	4d	7a	8c	6a
I-98	1e	2b	3e	8m	4d	7a	8c	6a
I-99	1e	2b	3k	8m	4d	7a	8c	6a
I-100	1e	2b	3b	8m	4d	7a	8c	6d
I-101	1e	2b	3e	8m	4d	7a	8c	6d
I-102	1e	2b	3k	8m	4d	7a	8c	6d
I-103	1e	2b	3b	8m	4d	7a	8e	6a
I-104	1e	2b	3e	8m	4d	7a	8e	6a
I-105	1e	2b	3k	8m	4d	7a	8e	6a
I-106	1e	2b	3b	8m	4d	7a	8e	6d
I-107	1e	2b	3e	8m	4d	7a	8e	6d
I-108	1e	2b	3k	8m	4d	7a	8e	6d
I-109	1e	2b	3b	8m	4d	7b	8c	6a
I-110	1e	2b	3e	8m	4d	7b	8c	6a
I-111	1e	2b	3k	8m	4d	7b	8c	6a
I-112	1e	2b	3b	8m	4d	7b	8c	6d
I-113	1e	2b	3e	8m	4d	7b	8c	6d
I-114	1e	2b	3k	8m	4d	7b	8c	6d
I-115	1e	2b	3b	8m	4d	7b	8e	6a
I-116	1e	2b	3e	8m	4d	7b	8e	6a
I-117	1e	2b	3k	8m	4d	7b	8e	6a
I-118	1e	2b	3b	8m	4d	7b	8e	6d
I-119	1e	2b	3e	8m	4d	7b	8e	6d
I-120	1e	2b	3k	8m	4d	7b	8e	6d
I-121	1e	2b	3b	8m	4f	7a	8c	6a
I-122	1e	2b	3e	8m	4f	7a	8c	6a
I-123	1e	2b	3k	8m	4f	7a	8c	6a
I-124	1e	2b	3b	8m	4f	7a	8c	6d
I-125	1e	2b	3e	8m	4f	7a	8c	6d
I-126	1e	2b	3k	8m	4f	7a	8c	6d
I-127	1e	2b	3b	8m	4f	7a	8e	6a
I-128	1e	2b	3e	8m	4f	7a	8e	6a
I-129	1e	2b	3k	8m	4f	7a	8e	6a
I-130	1e	2b	3b	8m	4f	7a	8e	6d
I-131	1e	2b	3e	8m	4f	7a	8e	6d
I-132	1e	2b	3k	8m	4f	7a	8e	6d
I-133	1e	2b	3b	8m	4f	7b	8c	6a
I-134	1e	2b	3e	8m	4f	7b	8c	6a
I-135	1e	2b	3k	8m	4f	7b	8c	6a
I-136	1e	2b	3b	8m	4f	7b	8c	6d
I-137	1e	2b	3e	8m	4f	7b	8c	6d
I-138	1e	2b	3k	8m	4f	7b	8c	6d
I-139	1e	2b	3b	8m	4f	7b	8e	6a
I-140	1e	2b	3e	8m	4f	7b	8e	6a
I-141	1e	2b	3k	8m	4f	7b	8e	6a
I-142	1e	2b	3b	8m	4f	7b	8e	6d
I-143	1e	2b	3e	8m	4f	7b	8e	6d
I-144	1e	2b	3k	8m	4f	7b	8e	6d
I-145	1e	2e	3b	8m	4d	7a	8c	6a
I-146	1e	2e	3e	8m	4d	7a	8c	6a
I-147	1e	2e	3k	8m	4d	7a	8c	6a
I-148	1e	2e	3b	8m	4d	7a	8c	6d
I-149	1e	2e	3e	8m	4d	7a	8c	6d
I-150	1e	2e	3k	8m	4d	7a	8c	6d
I-151	1e	2e	3b	8m	4d	7a	8e	6a
I-152	1e	2e	3e	8m	4d	7a	8e	6a
I-153	1e	2e	3k	8m	4d	7a	8e	6a
I-154	1e	2e	3b	8m	4d	7a	8e	6d
I-155	1e	2e	3e	8m	4d	7a	8e	6d
I-156	1e	2e	3k	8m	4d	7a	8e	6d
I-157	1e	2e	3b	8m	4d	7b	8c	6a
I-158	1e	2e	3e	8m	4d	7b	8c	6a
I-159	1e	2e	3k	8m	4d	7b	8c	6a
I-160	1e	2e	3b	8m	4d	7b	8c	6d
I-161	1e	2e	3e	8m	4d	7b	8c	6d
I-162	1e	2e	3k	8m	4d	7b	8c	6d
I-163	1e	2e	3b	8m	4d	7b	8e	6a
I-164	1e	2e	3e	8m	4d	7b	8e	6a
I-165	1e	2e	3k	8m	4d	7b	8e	6a
I-166	1e	2e	3b	8m	4d	7b	8e	6d
I-167	1e	2e	3e	8m	4d	7b	8e	6d
I-168	1e	2e	3k	8m	4d	7b	8e	6d
I-169	1e	2e	3b	8m	4f	7a	8c	6a
I-170	1e	2e	3e	8m	4f	7a	8c	6a
I-171	1e	2e	3k	8m	4f	7a	8c	6a
I-172	1e	2e	3b	8m	4f	7a	8c	6d
I-173	1e	2e	3e	8m	4f	7a	8c	6d
I-174	1e	2e	3k	8m	4f	7a	8c	6d
I-175	1e	2e	3b	8m	4f	7a	8e	6a
I-176	1e	2e	3e	8m	4f	7a	8e	6a
I-177	1e	2e	3k	8m	4f	7a	8e	6a
I-178	1e	2e	3b	8m	4f	7a	8e	6d
I-179	1e	2e	3e	8m	4f	7a	8e	6d
I-180	1e	2e	3k	8m	4f	7a	8e	6d
I-181	1e	2e	3b	8m	4f	7b	8c	6a
I-182	1e	2e	3e	8m	4f	7b	8c	6a
I-183	1e	2e	3k	8m	4f	7b	8c	6a
I-184	1e	2e	3b	8m	4f	7b	8c	6d
I-185	1e	2e	3e	8m	4f	7b	8c	6d
I-186	1e	2e	3k	8m	4f	7b	8c	6d
I-187	1e	2e	3b	8m	4f	7b	8e	6a
I-188	1e	2e	3e	8m	4f	7b	8e	6a
I-189	1e	2e	3k	8m	4f	7b	8e	6a
I-190	1e	2e	3b	8m	4f	7b	8e	6d
I-191	1e	2e	3e	8m	4f	7b	8e	6d
I-192	1e	2e	3k	8m	4f	7b	8e	6d
I-193	1b	2b	3b	8q	4d	7a	8c	6a
I-194	1b	2b	3e	8q	4d	7a	8c	6a
I-195	1b	2b	3k	8q	4d	7a	8c	6a
I-196	1b	2b	3b	8q	4d	7a	8c	6d
I-197	1b	2b	3e	8q	4d	7a	8c	6d
I-198	1b	2b	3k	8q	4d	7a	8c	6d
I-199	1b	2b	3b	8q	4d	7a	8e	6a
I-200	1b	2b	3e	8q	4d	7a	8e	6a
I-201	1b	2b	3k	8q	4d	7a	8e	6a
I-202	1b	2b	3b	8q	4d	7a	8e	6d
I-203	1b	2b	3e	8q	4d	7a	8e	6d
I-204	1b	2b	3k	8q	4d	7a	8e	6d
I-205	1b	2b	3b	8q	4d	7b	8c	6a
I-206	1b	2b	3e	8q	4d	7b	8c	6a
I-207	1b	2b	3k	8q	4d	7b	8c	6a
I-208	1b	2b	3b	8q	4d	7b	8c	6d
I-209	1b	2b	3e	8q	4d	7b	8c	6d
I-210	1b	2b	3k	8q	4d	7b	8c	6d
I-211	1b	2b	3b	8q	4d	7b	8e	6a
I-212	1b	2b	3e	8q	4d	7b	8e	6a
I-213	1b	2b	3k	8q	4d	7b	8e	6a
I-214	1b	2b	3b	8q	4d	7b	8e	6d
I-215	1b	2b	3e	8q	4d	7b	8e	6d
I-216	1b	2b	3k	8q	4d	7b	8e	6d
I-217	1b	2b	3b	8q	4f	7a	8c	6a
I-218	1b	2b	3e	8q	4f	7a	8c	6a
I-219	1b	2b	3k	8q	4f	7a	8c	6a
I-220	1b	2b	3b	8q	4f	7a	8c	6d
I-221	1b	2b	3e	8q	4f	7a	8c	6d
I-222	1b	2b	3k	8q	4f	7a	8c	6d
I-223	1b	2b	3b	8q	4f	7a	8e	6a
I-224	1b	2b	3e	8q	4f	7a	8e	6a
I-225	1b	2b	3k	8q	4f	7a	8e	6a
I-226	1b	2b	3b	8q	4f	7a	8e	6d
I-227	1b	2b	3e	8q	4f	7a	8e	6d
I-228	1b	2b	3k	8q	4f	7a	8e	6d
I-229	1b	2b	3b	8q	4f	7b	8c	6a
I-230	1b	2b	3e	8q	4f	7b	8c	6a
I-231	1b	2b	3k	8q	4f	7b	8c	6a
I-232	1b	2b	3b	8q	4f	7b	8c	6d
I-233	1b	2b	3e	8q	4f	7b	8c	6d
I-234	1b	2b	3k	8q	4f	7b	8c	6d
I-235	1b	2b	3b	8q	4f	7b	8e	6a
I-236	1b	2b	3e	8q	4f	7b	8e	6a
I-237	1b	2b	3k	8q	4f	7b	8e	6a
I-238	1b	2b	3b	8q	4f	7b	8e	6d
I-239	1b	2b	3e	8q	4f	7b	8e	6d
I-240	1b	2b	3k	8q	4f	7b	8e	6d
I-241	1b	2e	3b	8q	4d	7a	8c	6a
I-242	1b	2e	3e	8q	4d	7a	8c	6a
I-243	1b	2e	3k	8q	4d	7a	8c	6a
I-244	1b	2e	3b	8q	4d	7a	8c	6d
I-245	1b	2e	3e	8q	4d	7a	8c	6d
I-246	1b	2e	3k	8q	4d	7a	8c	6d
I-247	1b	2e	3b	8q	4d	7a	8e	6a
I-248	1b	2e	3e	8q	4d	7a	8e	6a
I-249	1b	2e	3k	8q	4d	7a	8e	6a
I-250	1b	2e	3b	8q	4d	7a	8e	6d
I-251	1b	2e	3e	8q	4d	7a	8e	6d
I-252	1b	2e	3k	8q	4d	7a	8e	6d
I-253	1b	2e	3b	8q	4d	7b	8c	6a
I-254	1b	2e	3e	8q	4d	7b	8c	6a
I-255	1b	2e	3k	8q	4d	7b	8c	6a
I-256	1b	2e	3b	8q	4d	7b	8c	6d
I-257	1b	2e	3e	8q	4d	7b	8c	6d
I-258	1b	2e	3k	8q	4d	7b	8c	6d
I-259	1b	2e	3b	8q	4d	7b	8e	6a
I-260	1b	2e	3e	8q	4d	7b	8e	6a
I-261	1b	2e	3k	8q	4d	7b	8e	6a
I-262	1b	2e	3b	8q	4d	7b	8e	6d
I-263	1b	2e	3e	8q	4d	7b	8e	6d
I-264	1b	2e	3k	8q	4d	7b	8e	6d
I-265	1b	2e	3b	8q	4f	7a	8c	6a
I-266	1b	2e	3e	8q	4f	7a	8c	6a
I-267	1b	2e	3k	8q	4f	7a	8c	6a
I-268	1b	2e	3b	8q	4f	7a	8c	6d
I-269	1b	2e	3e	8q	4f	7a	8c	6d
I-270	1b	2e	3k	8q	4f	7a	8c	6d
I-271	1b	2e	3b	8q	4f	7a	8e	6a
I-272	1b	2e	3e	8q	4f	7a	8e	6a
I-273	1b	2e	3k	8q	4f	7a	8e	6a
I-274	1b	2e	3b	8q	4f	7a	8e	6d
I-275	1b	2e	3e	8q	4f	7a	8e	6d
I-276	1b	2e	3k	8q	4f	7a	8e	6d
I-277	1b	2e	3b	8q	4f	7b	8c	6a
I-278	1b	2e	3e	8q	4f	7b	8c	6a
I-279	1b	2e	3k	8q	4f	7b	8c	6a
I-280	1b	2e	3b	8q	4f	7b	8c	6d
I-281	1b	2e	3e	8q	4f	7b	8c	6d
I-282	1b	2e	3k	8q	4f	7b	8c	6d
I-283	1b	2e	3b	8q	4f	7b	8e	6a
I-284	1b	2e	3e	8q	4f	7b	8e	6a
I-285	1b	2e	3k	8q	4f	7b	8e	6a
I-286	1b	2e	3b	8q	4f	7b	8e	6d
I-287	1b	2e	3e	8q	4f	7b	8e	6d
I-288	1b	2e	3k	8q	4f	7b	8e	6d
I-289	1e	2b	3b	8q	4d	7a	8c	6a
I-290	1e	2b	3e	8q	4d	7a	8c	6a
I-291	1e	2b	3k	8q	4d	7a	8c	6a
I-292	1e	2b	3b	8q	4d	7a	8c	6d
I-293	1e	2b	3e	8q	4d	7a	8c	6d
I-294	1e	2b	3k	8q	4d	7a	8c	6d
I-295	1e	2b	3b	8q	4d	7a	8e	6a
I-296	1e	2b	3e	8q	4d	7a	8e	6a
I-297	1e	2b	3k	8q	4d	7a	8e	6a
I-298	1e	2b	3b	8q	4d	7a	8e	6d
I-299	1e	2b	3e	8q	4d	7a	8e	6d
I-300	1e	2b	3k	8q	4d	7a	8e	6d
I-301	1e	2b	3b	8q	4d	7b	8c	6a
I-302	1e	2b	3e	8q	4d	7b	8c	6a
I-303	1e	2b	3k	8q	4d	7b	8c	6a
I-304	1e	2b	3b	8q	4d	7b	8c	6d
I-305	1e	2b	3e	8q	4d	7b	8c	6d
I-306	1e	2b	3k	8q	4d	7b	8c	6d
I-307	1e	2b	3b	8q	4d	7b	8e	6a
I-308	1e	2b	3e	8q	4d	7b	8e	6a
I-309	1e	2b	3k	8q	4d	7b	8e	6a
I-310	1e	2b	3b	8q	4d	7b	8e	6d
I-311	1e	2b	3e	8q	4d	7b	8e	6d
I-312	1e	2b	3k	8q	4d	7b	8e	6d
I-313	1e	2b	3b	8q	4f	7a	8c	6a
I-314	1e	2b	3e	8q	4f	7a	8c	6a
I-315	1e	2b	3k	8q	4f	7a	8c	6a
I-316	1e	2b	3b	8q	4f	7a	8c	6d
I-317	1e	2b	3e	8q	4f	7a	8c	6d
I-318	1e	2b	3k	8q	4f	7a	8c	6d
I-319	1e	2b	3b	8q	4f	7a	8e	6a
I-320	1e	2b	3e	8q	4f	7a	8e	6a
I-321	1e	2b	3k	8q	4f	7a	8e	6a
I-322	1e	2b	3b	8q	4f	7a	8e	6d
I-323	1e	2b	3e	8q	4f	7a	8e	6d
I-324	1e	2b	3k	8q	4f	7a	8e	6d
I-325	1e	2b	3b	8q	4f	7b	8c	6a
I-326	1e	2b	3e	8q	4f	7b	8c	6a
I-327	1e	2b	3k	8q	4f	7b	8c	6a
I-328	1e	2b	3b	8q	4f	7b	8c	6d
I-329	1e	2b	3e	8q	4f	7b	8c	6d
I-330	1e	2b	3k	8q	4f	7b	8c	6d
I-331	1e	2b	3b	8q	4f	7b	8e	6a
I-332	1e	2b	3e	8q	4f	7b	8e	6a
I-333	1e	2b	3k	8q	4f	7b	8e	6a
I-334	1e	2b	3b	8q	4f	7b	8e	6d
I-335	1e	2b	3e	8q	4f	7b	8e	6d
I-336	1e	2b	3k	8q	4f	7b	8e	6d
I-337	1e	2e	3b	8q	4d	7a	8c	6a
I-338	1e	2e	3e	8q	4d	7a	8c	6a
I-339	1e	2e	3k	8q	4d	7a	8c	6a
I-340	1e	2e	3b	8q	4d	7a	8c	6d
I-341	1e	2e	3e	8q	4d	7a	8c	6d
I-342	1e	2e	3k	8q	4d	7a	8c	6d
I-343	1e	2e	3b	8q	4d	7a	8e	6a
I-344	1e	2e	3e	8q	4d	7a	8e	6a
I-345	1e	2e	3k	8q	4d	7a	8e	6a
I-346	1e	2e	3b	8q	4d	7a	8e	6d
I-347	1e	2e	3e	8q	4d	7a	8e	6d
I-348	1e	2e	3k	8q	4d	7a	8e	6d
I-349	1e	2e	3b	8q	4d	7b	8c	6a
I-350	1e	2e	3e	8q	4d	7b	8c	6a
I-351	1e	2e	3k	8q	4d	7b	8c	6a
I-352	1e	2e	3b	8q	4d	7b	8c	6d
I-353	1e	2e	3e	8q	4d	7b	8c	6d
I-354	1e	2e	3k	8q	4d	7b	8c	6d
I-355	1e	2e	3b	8q	4d	7b	8e	6a
I-356	1e	2e	3e	8q	4d	7b	8e	6a
I-357	1e	2e	3k	8q	4d	7b	8e	6a
I-358	1e	2e	3b	8q	4d	7b	8e	6d
I-359	1e	2e	3e	8q	4d	7b	8e	6d
I-360	1e	2e	3k	8q	4d	7b	8e	6d
I-361	1e	2e	3b	8q	4f	7a	8c	6a
I-362	1e	2e	3e	8q	4f	7a	8c	6a
I-363	1e	2e	3k	8q	4f	7a	8c	6a
I-364	1e	2e	3b	8q	4f	7a	8c	6d
I-365	1e	2e	3e	8q	4f	7a	8c	6d
I-366	1e	2e	3k	8q	4f	7a	8c	6d
I-367	1e	2e	3b	8q	4f	7a	8e	6a
I-368	1e	2e	3e	8q	4f	7a	8e	6a
I-369	1e	2e	3k	8q	4f	7a	8e	6a
I-370	1e	2e	3b	8q	4f	7a	8e	6d
I-371	1e	2e	3e	8q	4f	7a	8e	6d
I-372	1e	2e	3k	8q	4f	7a	8e	6d
I-373	1e	2e	3b	8q	4f	7b	8c	6a
I-374	1e	2e	3e	8q	4f	7b	8c	6a
I-375	1e	2e	3k	8q	4f	7b	8c	6a
I-376	1e	2e	3b	8q	4f	7b	8c	6d
I-377	1e	2e	3e	8q	4f	7b	8c	6d
I-378	1e	2e	3k	8q	4f	7b	8c	6d
I-379	1e	2e	3b	8q	4f	7b	8e	6a
I-380	1e	2e	3e	8q	4f	7b	8e	6a
I-381	1e	2e	3k	8q	4f	7b	8e	6a
I-382	1e	2e	3b	8q	4f	7b	8e	6d
I-383	1e	2e	3e	8q	4f	7b	8e	6d
I-384	1e	2e	3k	8q	4f	7b	8e	6d

In embodiment (2) of the first aspect, the invention comprises the compound of formula (II), or any one of formulae (IIa)-(IIe),
and pharmaceutically acceptable salts thereof, wherein p is 0 or 1; R²⁶is —C₁-C₇alkyl-R⁹, aryl-R⁹, aryl(C₁-C₇) alkyl-R⁹, or -heteroaryl-R⁹, and m, n, X, Y, L¹, R¹-R⁶, R⁹, R¹⁵, and R³¹are as defined for formula (I).
The invention further comprises subgenera of embodiment (2) of the first aspect in which the substituents are selected as any and all combinations of m, n, L¹, R¹, R², R⁴, R⁵, R⁶, R¹⁵, R²⁰, R³¹, X, and Y as defined herein, including without limitation, the following:
R¹is one of groups (1a)-(1l) as defined above for formula (I).
R²is one of groups (2a)-(2j) as defined above for formula (I).
R⁴is one of groups (3a)-(3k) as defined above for formula (I).
R⁵is one of groups (8h)-(8l) as defined above for formula (I).
each R⁶is independently one of groups (8m)-(8q) as defined above for formula (I).
L¹is one of groups (5v)-(5z) as defined above for formula (I).
X and Y are one of groups (7a)-(7g) as defined above for formula (I).
m and n are one of groups (8a)-(8g) as defined above for formula (I).
each R³is independently one of the following groups (9a)-(9e):

- (9a) hydrogen, —C₁-C₇alkyl, —C₁-C₇alkylaryl, or —C₁-C₇alkylheteroaryl.
- (9b) hydrogen, methyl, ethyl, t-butyl, or benzyl.
- (9c) benzyl.
- (9d) hydrogen or benzyl.
- (9e) hydrogen.

R¹⁵and R³¹are each independently one of the following groups (10a)-(10e):

- (10a) hydrogen, —C₁-C₇alkyl, or benzyl.
- (10b) hydrogen or —C₁-C7 alkyl.
- (10c) hydrogen or methyl.
- (10d) hydrogen.
- (10e) methyl

R²⁰is one of the following groups (11a) (11gg):

- (11a) R²⁰is —C₁-C₇alkyl-R⁹, -aryl(C₁-C₇) alkyl-R⁹, or -heteroaryl-R⁹.
- (11b) R²⁰is —C₁-C₇alkyl-R⁹or -aryl(C₁-C₇) alkyl-R⁹.
- (11e) R²⁰is -heteroaryl-R⁹.
- (11d) R²⁰is -pyridyl-R⁹.
- (11e) R²⁰is -pyrimiclinyl-R⁹.
- (11f) R²⁰is —C₁-C₇alkyl-R⁹.
- (11g) R²⁰is —C₁-C₇alkyl-R⁹, -aryl(C₁-C₇) alkyl-R⁹, or -heteroaryl-R⁹.
- (11h) R²⁰is —C₁-C₇alkyl-R⁹.
- (11i) R²⁰is selected from the group consisting of,

wherein Z¹is a fluoro cold standard and t is 0, 1, 2, 3, 4, or 5.

- (11j) R²⁰is selected from the group consisting of,

wherein Z¹is a fluoro cold standard.

- (11k) R²⁰is selected from the group consisting of,

wherein Z²is fluoro cold standard, .

- (11l) R²⁰is selected from the group consisting of,

- (11m)
  wherein Z²is a fluoro cold standard. R²⁰is selected from the goup consisting of,

wherein t is 0, 1, 2, 3, 4, or 5.

- (11n) R²⁰is selected from the group consisting of,

wherein t is 0, 1, 2, 3, 4, or 5.

- (11o) R²⁰is selected from the group consisting of,

(11p) R²⁰is selected from the group consisting of,

- (11q) R²⁰is

wherein t is 0, 1, 2, 3, 4, or 5.

- (11r) R²⁰is

- (11s) R²⁰is

- (11t) R²⁰is

- (11u) R²⁰is

- (11v) R²⁰is

Particular embodiments of this aspect of the invention include compounds of any one of formulae (II) and (IIa)-(IIe) wherein are defined in each of the following rows, wherein each entry is a group number as defined above:


Embodiment	R¹, R², R⁴, R⁵	R³	R⁶	L¹	R²⁰	R³¹

II-1	1b, 2b, 3b, 8h	9a	8m	5v	11a	10c
II-2	1b, 2b, 3b, 8h	9a	8m	5v	11b	10c
II-3	1b, 2b, 3b, 8h	9a	8m	5v	11c	10c
II-4	1b, 2b, 3b, 8h	9a	8m	5v	11d	10c
II-5	1b, 2b, 3b, 8h	9a	8m	5v	11e	10c
II-6	1b, 2b, 3b, 8h	9a	8m	5v	11f	10c
II-7	1b, 2b, 3b, 8h	9a	8m	5v	11g	10c
II-8	1b, 2b, 3b, 8h	9a	8m	5v	11h	10c
II-9	1b, 2b, 3b, 8h	9a	8m	5v	11i	10c
II-10	1b, 2b, 3b, 8h	9a	8m	5v	11j	10c
II-11	1b, 2b, 3b, 8h	9a	8m	5v	11k	10c
II-12	1b, 2b, 3b, 8h	9a	8m	5v	11l	10c
II-13	1b, 2b, 3b, 8h	9a	8m	5v	11m	10c
II-14	1b, 2b, 3b, 8h	9a	8m	5v	11n	10c
II-15	1b, 2b, 3b, 8h	9a	8m	5v	11o	10c
II-16	1b, 2b, 3b, 8h	9a	8m	5v	11p	10c
II-17	1b, 2b, 3b, 8h	9a	8m	5v	11q	10c
II-18	1b, 2b, 3b, 8h	9a	8m	5v	11r	10c
II-19	1b, 2b, 3b, 8h	9a	8m	5v	11s	10c
II-20	1b, 2b, 3b, 8h	9a	8m	5v	11t	10c
II-21	1b, 2b, 3b, 8h	9a	8m	5v	11u	10c
II-22	1b, 2b, 3b, 8h	9a	8m	5v	11v	10c
II-23	1b, 2b, 3b, 8h	9a	8m	5v	11w	10c
II-24	1b, 2b, 3b, 8h	9a	8m	5v	11x	10c
II-25	1b, 2b, 3b, 8h	9a	8m	5v	11y	10c
II-26	1b, 2b, 3b, 8h	9a	8m	5v	11z	10c
II-27	1b, 2b, 3b, 8h	9a	8m	5v	11aa	10c
II-28	1b, 2b, 3b, 8h	9a	8m	5v	11bb	10c
II-29	1b, 2b, 3b, 8h	9a	8m	5v	11cc	10c
II-30	1b, 2b, 3b, 8h	9a	8m	5v	11dd	10c
II-31	1b, 2b, 3b, 8h	9a	8m	5v	11ee	10c
II-32	1b, 2b, 3b, 8h	9a	8m	5v	11ff	10c
II-33	1b, 2b, 3b, 8h	9a	8m	5v	11gg	10c
II-34	1b, 2b, 3b, 8h	9a	8q	5v	11a	10c
II-35	1b, 2b, 3b, 8h	9a	8q	5v	11b	10c
II-36	1b, 2b, 3b, 8h	9a	8q	5v	11c	10c
II-37	1b, 2b, 3b, 8h	9a	8q	5v	11d	10c
II-38	1b, 2b, 3b, 8h	9a	8q	5v	11e	10c
II-39	1b, 2b, 3b, 8h	9a	8q	5v	11f	10c
II-40	1b, 2b, 3b, 8h	9a	8q	5v	11g	10c
II-41	1b, 2b, 3b, 8h	9a	8q	5v	11h	10c
II-42	1b, 2b, 3b, 8h	9a	8q	5v	11i	10c
II-43	1b, 2b, 3b, 8h	9a	8q	5v	11j	10c
II-44	1b, 2b, 3b, 8h	9a	8q	5v	11k	10c
II-45	1b, 2b, 3b, 8h	9a	8q	5v	11l	10c
II-46	1b, 2b, 3b, 8h	9a	8q	5v	11m	10c
II-47	1b, 2b, 3b, 8h	9a	8q	5v	11n	10c
II-48	1b, 2b, 3b, 8h	9a	8q	5v	11o	10c
II-49	1b, 2b, 3b, 8h	9a	8q	5v	11p	10c
II-50	1b, 2b, 3b, 8h	9a	8q	5v	11q	10c
II-51	1b, 2b, 3b, 8h	9a	8q	5v	11r	10c
II-52	1b, 2b, 3b, 8h	9a	8q	5v	11s	10c
II-53	1b, 2b, 3b, 8h	9a	8q	5v	11t	10c
II-54	1b, 2b, 3b, 8h	9a	8q	5v	11u	10c
II-55	1b, 2b, 3b, 8h	9a	8q	5v	11v	10c
II-56	1b, 2b, 3b, 8h	9a	8q	5v	11w	10c
II-57	1b, 2b, 3b, 8h	9a	8q	5v	11x	10c
II-58	1b, 2b, 3b, 8h	9a	8q	5v	11y	10c
II-59	1b, 2b, 3b, 8h	9a	8q	5v	11z	10c
II-60	1b, 2b, 3b, 8h	9a	8q	5v	11aa	10c
II-61	1b, 2b, 3b, 8h	9a	8q	5v	11bb	10c
II-62	1b, 2b, 3b, 8h	9a	8q	5v	11cc	10c
II-63	1b, 2b, 3b, 8h	9a	8q	5v	11dd	10c
II-64	1b, 2b, 3b, 8h	9a	8q	5v	11ee	10c
II-65	1b, 2b, 3b, 8h	9a	8q	5v	11ff	10c
II-66	1b, 2b, 3b, 8h	9a	8q	5v	11gg	10c
II-67	1b, 2b, 3b, 8h	9d	8m	5v	11a	10c
II-68	1b, 2b, 3b, 8h	9d	8m	5v	11b	10c
II-69	1b, 2b, 3b, 8h	9d	8m	5v	11c	10c
II-70	1b, 2b, 3b, 8h	9d	8m	5v	11d	10c
II-71	1b, 2b, 3b, 8h	9d	8m	5v	11e	10c
II-72	1b, 2b, 3b, 8h	9d	8m	5v	11f	10c
II-73	1b, 2b, 3b, 8h	9d	8m	5v	11g	10c
II-74	1b, 2b, 3b, 8h	9d	8m	5v	11h	10c
II-75	1b, 2b, 3b, 8h	9d	8m	5v	11i	10c
II-76	1b, 2b, 3b, 8h	9d	8m	5v	11j	10c
II-77	1b, 2b, 3b, 8h	9d	8m	5v	11k	10c
II-78	1b, 2b, 3b, 8h	9d	8m	5v	11l	10c
II-79	1b, 2b, 3b, 8h	9d	8m	5v	11m	10c
II-80	1b, 2b, 3b, 8h	9d	8m	5v	11n	10c
II-81	1b, 2b, 3b, 8h	9d	8m	5v	11o	10c
II-82	1b, 2b, 3b, 8h	9d	8m	5v	11p	10c
II-83	1b, 2b, 3b, 8h	9d	8m	5v	11q	10c
II-84	1b, 2b, 3b, 8h	9d	8m	5v	11r	10c
II-85	1b, 2b, 3b, 8h	9d	8m	5v	11s	10c
II-86	1b, 2b, 3b, 8h	9d	8m	5v	11t	10c
II-87	1b, 2b, 3b, 8h	9d	8m	5v	11u	10c
II-88	1b, 2b, 3b, 8h	9d	8m	5v	11v	10c
II-89	1b, 2b, 3b, 8h	9d	8m	5v	11w	10c
II-90	1b, 2b, 3b, 8h	9d	8m	5v	11x	10c
II-91	1b, 2b, 3b, 8h	9d	8m	5v	11y	10c
II-92	1b, 2b, 3b, 8h	9d	8m	5v	11z	10c
II-93	1b, 2b, 3b, 8h	9d	8m	5v	11aa	10c
II-94	1b, 2b, 3b, 8h	9d	8m	5v	11bb	10c
II-95	1b, 2b, 3b, 8h	9d	8m	5v	11cc	10c
II-96	1b, 2b, 3b, 8h	9d	8m	5v	11dd	10c
II-97	1b, 2b, 3b, 8h	9d	8m	5v	11ee	10c
II-98	1b, 2b, 3b, 8h	9d	8m	5v	11ff	10c
II-99	1b, 2b, 3b, 8h	9d	8m	5v	11gg	10c
II-100	1b, 2b, 3b, 8h	9d	8q	5v	11a	10c
II-101	1b, 2b, 3b, 8h	9d	8q	5v	11b	10c
II-102	1b, 2b, 3b, 8h	9d	8q	5v	11c	10c
II-103	1b, 2b, 3b, 8h	9d	8q	5v	11d	10c
II-104	1b, 2b, 3b, 8h	9d	8q	5v	11e	10c
II-105	1b, 2b, 3b, 8h	9d	8q	5v	11f	10c
II-106	1b, 2b, 3b, 8h	9d	8q	5v	11g	10c
II-107	1b, 2b, 3b, 8h	9d	8q	5v	11h	10c
II-108	1b, 2b, 3b, 8h	9d	8q	5v	11i	10c
II-109	1b, 2b, 3b, 8h	9d	8q	5v	11j	10c
II-110	1b, 2b, 3b, 8h	9d	8q	5v	11k	110c
II-111	1b, 2b, 3b, 8h	9d	8q	5v	11l	10c
II-112	1b, 2b, 3b, 8h	9d	8q	5v	11m	10c
II-113	1b, 2b, 3b, 8h	9d	8q	5v	11n	10c
II-114	1b, 2b, 3b, 8h	9d	8q	5v	11o	10c
II-115	1b, 2b, 3b, 8h	9d	8q	5v	11p	10c
II-116	1b, 2b, 3b, 8h	9d	8q	5v	11q	10c
II-117	1b, 2b, 3b, 8h	9d	8q	5v	11r	10c
II-118	1b, 2b, 3b, 8h	9d	8q	5v	11s	10c
II-119	1b, 2b, 3b, 8h	9d	8q	5v	11t	10c
II-120	1b, 2b, 3b, 8h	9d	8q	5v	11u	10c
II-121	1b, 2b, 3b, 8h	9d	8q	5v	11v	10c
II-122	1b, 2b, 3b, 8h	9d	8q	5v	11w	10c
II-123	1b, 2b, 3b, 8h	9d	8q	5v	11x	10c
II-124	1b, 2b, 3b, 8h	9d	8q	5v	11y	10c
II-125	1b, 2b, 3b, 8h	9d	8q	5v	11z	10c
II-126	1b, 2b, 3b, 8h	9d	8q	5v	11aa	10c
II-127	1b, 2b, 3b, 8h	9d	8q	5v	11bb	10c
II-128	1b, 2b, 3b, 8h	9d	8q	5v	11cc	10c
II-129	1b, 2b, 3b, 8h	9d	8q	5v	11dd	10c
II-130	1b, 2b, 3b, 8h	9d	8q	5v	11ee	10c
II-131	1b, 2b, 3b, 8h	9d	8q	5v	11ff	10c
II-132	1b, 2b, 3b, 8h	9d	8q	5v	11gg	10c
II-133	1e, 2e, 3e, 8k	9a	8m	5v	11a	10c
II-134	1e, 2e, 3e, 8k	9a	8m	5v	11b	10c
II-135	1e, 2e, 3e, 8k	9a	8m	5v	11c	10c
II-136	1e, 2e, 3e, 8k	9a	8m	5v	11d	10c
II-137	1e, 2e, 3e, 8k	9a	8m	5v	11e	10c
II-138	1e, 2e, 3e, 8k	9a	8m	5v	11f	10c
II-139	1e, 2e, 3e, 8k	9a	8m	5v	11g	10c
II-140	1e, 2e, 3e, 8k	9a	8m	5v	11h	10c
II-141	1e, 2e, 3e, 8k	9a	8m	5v	11i	10c
II-142	1e, 2e, 3e, 8k	9a	8m	5v	11j	10c
II-143	1e, 2e, 3e, 8k	9a	8m	5v	11k	10c
II-144	1e, 2e, 3e, 8k	9a	8m	5v	11l	10c
II-145	1e, 2e, 3e, 8k	9a	8m	5v	11m	10c
II-146	1e, 2e, 3e, 8k	9a	8m	5v	11n	10c
II-147	1e, 2e, 3e, 8k	9a	8m	5v	11o	10c
II-148	1e, 2e, 3e, 8k	9a	8m	5v	11p	10c
II-149	1e, 2e, 3e, 8k	9a	8m	5v	11q	10c
II-150	1e, 2e, 3e, 8k	9a	8m	5v	11r	10c
II-151	1e, 2e, 3e, 8k	9a	8m	5v	11s	10c
II-152	1e, 2e, 3e, 8k	9a	8m	5v	11t	10c
II-153	1e, 2e, 3e, 8k	9a	8m	5v	11u	10c
II-154	1e, 2e, 3e, 8k	9a	8m	5v	11v	10c
II-155	1e, 2e, 3e, 8k	9a	8m	5v	11w	10c
II-156	1e, 2e, 3e, 8k	9a	8m	5v	11x	10c
II-157	1e, 2e, 3e, 8k	9a	8m	5v	11y	10c
II-158	1e, 2e, 3e, 8k	9a	8m	5v	11z	10c
II-159	1e, 2e, 3e, 8k	9a	8m	5v	11aa	10c
II-160	1e, 2e, 3e, 8k	9a	8m	5v	11bb	10c
II-161	1e, 2e, 3e, 8k	9a	8m	5v	11cc	10c
II-162	1e, 2e, 3e, 8k	9a	8m	5v	11dd	10c
II-163	1e, 2e, 3e, 8k	9a	8m	5v	11ee	10c
II-164	1e, 2e, 3e, 8k	9a	8m	5v	11ff	10c
II-165	1e, 2e, 3e, 8k	9a	8m	5v	11gg	10c
II-166	1e, 2e, 3e, 8k	9a	8q	5v	11a	10c
II-167	1e, 2e, 3e, 8k	9a	8q	5v	11b	10c
II-168	1e, 2e, 3e, 8k	9a	8q	5v	11c	10c
II-169	1e, 2e, 3e, 8k	9a	8q	5v	11d	10c
II-170	1e, 2e, 3e, 8k	9a	8q	5v	11e	10c
II-171	1e, 2e, 3e, 8k	9a	8q	5v	11f	10c
II-172	1e, 2e, 3e, 8k	9a	8q	5v	11g	10c
II-173	1e, 2e, 3e, 8k	9a	8q	5v	11h	10c
II-174	1e, 2e, 3e, 8k	9a	8q	5v	11i	10c
II-175	1e, 2e, 3e, 8k	9a	8q	5v	11j	10c
II-176	1e, 2e, 3e, 8k	9a	8q	5v	11k	10c
II-177	1e, 2e, 3e, 8k	9a	8q	5v	11l	10c
II-178	1e, 2e, 3e, 8k	9a	8q	5v	11m	10c
II-179	1e, 2e, 3e, 8k	9a	8q	5v	11n	10c
II-180	1e, 2e, 3e, 8k	9a	8q	5v	11o	10c
II-181	1e, 2e, 3e, 8k	9a	8q	5v	11p	10c
II-182	1e, 2e, 3e, 8k	9a	8q	5v	11q	10c
II-183	1e, 2e, 3e, 8k	9a	8q	5v	11r	10c
II-184	1e, 2e, 3e, 8k	9a	8q	5v	11s	10c
II-185	1e, 2e, 3e, 8k	9a	8q	5v	11t	10c
II-186	1e, 2e, 3e, 8k	9a	8q	5v	11u	10c
II-187	1e, 2e, 3e, 8k	9a	8q	5v	11v	10c
II-188	1e, 2e, 3e, 8k	9a	8q	5v	11w	10c
II-189	1e, 2e, 3e, 8k	9a	8q	5v	11x	10c
II-190	1e, 2e, 3e, 8k	9a	8q	5v	11y	10c
II-191	1e, 2e, 3e, 8k	9a	8q	5v	11z	10c
II-192	1e, 2e, 3e, 8k	9a	8q	5v	11aa	10c
II-193	1e, 2e, 3e, 8k	9a	8q	5v	11bb	10c
II-194	1e, 2e, 3e, 8k	9a	8q	5v	11cc	10c
II-195	1e, 2e, 3e, 8k	9a	8q	5v	11dd	10c
II-196	1e, 2e, 3e, 8k	9a	8q	5v	11ee	10c
II-197	1e, 2e, 3e, 8k	9a	8q	5v	11ff	10c
II-198	1e, 2e, 3e, 8k	9a	8q	5v	11gg	10c
II-199	1e, 2e, 3e, 8k	9d	8m	5v	11a	10c
II-200	1e, 2e, 3e, 8k	9d	8m	5v	11b	10c
II-201	1e, 2e, 3e, 8k	9d	8m	5v	11c	10c
II-202	1e, 2e, 3e, 8k	9d	8m	5v	11d	10c
II-203	1e, 2e, 3e, 8k	9d	8m	5v	11e	10c
II-204	1e, 2e, 3e, 8k	9d	8m	5v	11f	10c
II-205	1e, 2e, 3e, 8k	9d	8m	5v	11g	10c
II-206	1e, 2e, 3e, 8k	9d	8m	5v	11h	10c
II-207	1e, 2e, 3e, 8k	9d	8m	5v	11i	10c
II-208	1e, 2e, 3e, 8k	9d	8m	5v	11j	10c
II-209	1e, 2e, 3e, 8k	9d	8m	5v	11k	10c
II-210	1e, 2e, 3e, 8k	9d	8m	5v	11l	10c
II-211	1e, 2e, 3e, 8k	9d	8m	5v	11m	10c
II-212	1e, 2e, 3e, 8k	9d	8m	5v	11n	10c
II-213	1e, 2e, 3e, 8k	9d	8m	5v	11o	10c
II-214	1e, 2e, 3e, 8k	9d	8m	5v	11p	10c
II-215	1e, 2e, 3e, 8k	9d	8m	5v	11q	10c
II-216	1e, 2e, 3e, 8k	9d	8m	5v	11r	10c
II-217	1e, 2e, 3e, 8k	9d	8m	5v	11s	10c
II-218	1e, 2e, 3e, 8k	9d	8m	5v	11t	10c
II-219	1e, 2e, 3e, 8k	9d	8m	5v	11u	10c
II-220	1e, 2e, 3e, 8k	9d	8m	5v	11v	10c
II-221	1e, 2e, 3e, 8k	9d	8m	5v	11w	10c
II-222	1e, 2e, 3e, 8k	9d	8m	5v	11x	10c
II-223	1e, 2e, 3e, 8k	9d	8m	5v	11y	10c
II-224	1e, 2e, 3e, 8k	9d	8m	5v	11z	10c
II-225	1e, 2e, 3e, 8k	9d	8m	5v	11aa	10c
II-226	1e, 2e, 3e, 8k	9d	8m	5v	11bb	10c
II-227	1e, 2e, 3e, 8k	9d	8m	5v	11cc	10c
II-228	1e, 2e, 3e, 8k	9d	8m	5v	11dd	10c
II-229	1e, 2e, 3e, 8k	9d	8m	5v	11ee	10c
II-230	1e, 2e, 3e, 8k	9d	8m	5v	11ff	10c
II-231	1e, 2e, 3e, 8k	9d	8m	5v	11gg	10c
II-232	1e, 2e, 3e, 8k	9d	8q	5v	11a	10c
II-233	1e, 2e, 3e, 8k	9d	8q	5v	11b	10c
II-234	1e, 2e, 3e, 8k	9d	8q	5v	11c	10c
II-235	1e, 2e, 3e, 8k	9d	8q	5v	11d	10c
II-236	1e, 2e, 3e, 8k	9d	8q	5v	11e	10c
II-237	1e, 2e, 3e, 8k	9d	8q	5v	11f	10c
II-238	1e, 2e, 3e, 8k	9d	8q	5v	11g	10c
II-239	1e, 2e, 3e, 8k	9d	8q	5v	11h	10c
II-240	1e, 2e, 3e, 8k	9d	8q	5v	11i	10c
II-241	1e, 2e, 3e, 8k	9d	8q	5v	11j	10c
II-242	1e, 2e, 3e, 8k	9d	8q	5v	11k	10c
II-243	1e, 2e, 3e, 8k	9d	8q	5v	11l	10c
II-244	1e, 2e, 3e, 8k	9d	8q	5v	11m	10c
II-245	1e, 2e, 3e, 8k	9d	8q	5v	11n	10c
II-246	1e, 2e, 3e, 8k	9d	8q	5v	11o	10c
II-247	1e, 2e, 3e, 8k	9d	8q	5v	11p	10c
II-248	1e, 2e, 3e, 8k	9d	8q	5v	11q	10c
II-249	1e, 2e, 3e, 8k	9d	8q	5v	11r	10c
II-250	1e, 2e, 3e, 8k	9d	8q	5v	11s	10c
II-251	1e, 2e, 3e, 8k	9d	8q	5v	11t	10c
II-252	1e, 2e, 3e, 8k	9d	8q	5v	11u	10c
II-253	1e, 2e, 3e, 8k	9d	8q	5v	11v	10c
II-254	1e, 2e, 3e, 8k	9d	8q	5v	11w	10c
II-255	1e, 2e, 3e, 8k	9d	8q	5v	11x	10c
II-256	1e, 2e, 3e, 8k	9d	8q	5v	11y	10c
II-257	1e, 2e, 3e, 8k	9d	8q	5v	11z	10c
II-258	1e, 2e, 3e, 8k	9d	8q	5v	11aa	10c
II-259	1e, 2e, 3e, 8k	9d	8q	5v	11bb	10c
II-260	1e, 2e, 3e, 8k	9d	8q	5v	11cc	10c
II-261	1e, 2e, 3e, 8k	9d	8q	5v	11dd	10c
II-262	1e, 2e, 3e, 8k	9d	8q	5v	11ee	10c
II-263	1e, 2e, 3e, 8k	9d	8q	5v	11ff	10c
II-264	1e, 2e, 3e, 8k	9d	8q	5v	11gg	10c
II-265	1b, 2b, 3b, 8h	9a	8m	5y	11a	10c
II-266	1b, 2b, 3b, 8h	9a	8m	5y	11b	10c
II-267	1b, 2b, 3b, 8h	9a	8m	5y	11c	10c
II-268	1b, 2b, 3b, 8h	9a	8m	5y	11d	10c
II-269	1b, 2b, 3b, 8h	9a	8m	5y	11e	10c
II-270	1b, 2b, 3b, 8h	9a	8m	5y	11f	10c
II-271	1b, 2b, 3b, 8h	9a	8m	5y	11g	10c
II-272	1b, 2b, 3b, 8h	9a	8m	5y	11h	10c
II-273	1b, 2b, 3b, 8h	9a	8m	5y	11i	10c
II-274	1b, 2b, 3b, 8h	9a	8m	5y	11j	10c
II-275	1b, 2b, 3b, 8h	9a	8m	5y	11k	10c
II-276	1b, 2b, 3b, 8h	9a	8m	5y	11l	10c
II-277	1b, 2b, 3b, 8h	9a	8m	5y	11m	10c
II-278	1b, 2b, 3b, 8h	9a	8m	5y	11n	10c
II-279	1b, 2b, 3b, 8h	9a	8m	5y	11o	10c
II-280	1b, 2b, 3b, 8h	9a	8m	5y	11p	10c
II-281	1b, 2b, 3b, 8h	9a	8m	5y	11q	10c
II-282	1b, 2b, 3b, 8h	9a	8m	5y	11r	10c
II-283	1b, 2b, 3b, 8h	9a	8m	5y	11s	10c
II-284	1b, 2b, 3b, 8h	9a	8m	5y	11t	10c
II-285	1b, 2b, 3b, 8h	9a	8m	5y	11u	10c
II-286	1b, 2b, 3b, 8h	9a	8m	5y	11v	10c
II-287	1b, 2b, 3b, 8h	9a	8m	5y	11w	10c
II-288	1b, 2b, 3b, 8h	9a	8m	5y	11x	10c
II-289	1b, 2b, 3b, 8h	9a	8m	5y	11y	10c
II-290	1b, 2b, 3b, 8h	9a	8m	5y	11z	10c
II-291	1b, 2b, 3b, 8h	9a	8m	5y	11aa	10c
II-292	1b, 2b, 3b, 8h	9a	8m	5y	11bb	10c
II-293	1b, 2b, 3b, 8h	9a	8m	5y	11cc	10c
II-294	1b, 2b, 3b, 8h	9a	8m	5y	11dd	10c
II-295	1b, 2b, 3b, 8h	9a	8m	5y	11ee	10c
II-296	1b, 2b, 3b, 8h	9a	8m	5y	11ff	10c
II-297	1b, 2b, 3b, 8h	9a	8m	5y	11gg	10c
II-298	1b, 2b, 3b, 8h	9a	8q	5y	11a	10c
II-299	1b, 2b, 3b, 8h	9a	8q	5y	11b	10c
II-300	1b, 2b, 3b, 8h	9a	8q	5y	11c	10c
II-301	1b, 2b, 3b, 8h	9a	8q	5y	11d	10c
II-302	1b, 2b, 3b, 8h	9a	8q	5y	11e	10c
II-303	1b, 2b, 3b, 8h	9a	8q	5y	11f	10c
II-304	1b, 2b, 3b, 8h	9a	8q	5y	11g	10c
II-305	1b, 2b, 3b, 8h	9a	8q	5y	11h	10c
II-306	1b, 2b, 3b, 8h	9a	8q	5y	11i	10c
II-307	1b, 2b, 3b, 8h	9a	8q	5y	11j	10c
II-308	1b, 2b, 3b, 8h	9a	8q	5y	11k	10c
II-309	1b, 2b, 3b, 8h	9a	8q	5y	11l	10c
II-310	1b, 2b, 3b, 8h	9a	8q	5y	11m	10c
II-311	1b, 2b, 3b, 8h	9a	8q	5y	11n	10c
II-312	1b, 2b, 3b, 8h	9a	8q	5y	11o	10c
II-313	1b, 2b, 3b, 8h	9a	8q	5y	11p	10c
II-314	1b, 2b, 3b, 8h	9a	8q	5y	11q	10c
II-315	1b, 2b, 3b, 8h	9a	8q	5y	11r	10c
II-316	1b, 2b, 3b, 8h	9a	8q	5y	11s	10c
II-317	1b, 2b, 3b, 8h	9a	8q	5y	11t	10c
II-318	1b, 2b, 3b, 8h	9a	8q	5y	11u	10c
II-319	1b, 2b, 3b, 8h	9a	8q	5y	11v	10c
II-320	1b, 2b, 3b, 8h	9a	8q	5y	11w	10c
II-321	1b, 2b, 3b, 8h	9a	8q	5y	11x	10c
II-322	1b, 2b, 3b, 8h	9a	8q	5y	11y	10c
II-323	1b, 2b, 3b, 8h	9a	8q	5y	11z	10c
II-324	1b, 2b, 3b, 8h	9a	8q	5y	11aa	10c
II-325	1b, 2b, 3b, 8h	9a	8q	5y	11bb	10c
II-326	1b, 2b, 3b, 8h	9a	8q	5y	11cc	10c
II-327	1b, 2b, 3b, 8h	9a	8q	5y	11dd	10c
II-328	1b, 2b, 3b, 8h	9a	8q	5y	11ee	10c
II-329	1b, 2b, 3b, 8h	9a	8q	5y	11ff	10c
II-330	1b, 2b, 3b, 8h	9a	8q	5y	11gg	10c
II-331	1b, 2b, 3b, 8h	9d	8m	5y	11a	10c
II-332	1b, 2b, 3b, 8h	9d	8m	5y	11b	10c
II-333	1b, 2b, 3b, 8h	9d	8m	5y	11c	10c
II-334	1b, 2b, 3b, 8h	9d	8m	5y	11d	10c
II-335	1b, 2b, 3b, 8h	9d	8m	5y	11e	10c
II-336	1b, 2b, 3b, 8h	9d	8m	5y	11f	10c
II-337	1b, 2b, 3b, 8h	9d	8m	5y	11g	10c
II-338	1b, 2b, 3b, 8h	9d	8m	5y	11h	10c
II-339	1b, 2b, 3b, 8h	9d	8m	5y	11i	10c
II-340	1b, 2b, 3b, 8h	9d	8m	5y	11j	10c
II-341	1b, 2b, 3b, 8h	9d	8m	5y	11k	10c
II-342	1b, 2b, 3b, 8h	9d	8m	5y	11l	10c
II-343	1b, 2b, 3b, 8h	9d	8m	5y	11m	10c
II-344	1b, 2b, 3b, 8h	9d	8m	5y	11n	10c
II-345	1b, 2b, 3b, 8h	9d	8m	5y	11o	10c
II-346	1b, 2b, 3b, 8h	9d	8m	5y	11p	10c
II-347	1b, 2b, 3b, 8h	9d	8m	5y	11q	10c
II-348	1b, 2b, 3b, 8h	9d	8m	5y	11r	10c
II-349	1b, 2b, 3b, 8h	9d	8m	5y	11s	10c
II-350	1b, 2b, 3b, 8h	9d	8m	5y	11t	10c
II-351	1b, 2b, 3b, 8h	9d	8m	5y	11u	10c
II-352	1b, 2b, 3b, 8h	9d	8m	5y	11v	10c
II-353	1b, 2b, 3b, 8h	9d	8m	5y	11w	10c
II-354	1b, 2b, 3b, 8h	9d	8m	5y	11x	10c
II-355	1b, 2b, 3b, 8h	9d	8m	5y	11y	10c
II-356	1b, 2b, 3b, 8h	9d	8m	5y	11z	10c
II-357	1b, 2b, 3b, 8h	9d	8m	5y	11aa	10c
II-358	1b, 2b, 3b, 8h	9d	8m	5y	11bb	10c
II-359	1b, 2b, 3b, 8h	9d	8m	5y	11cc	10c
II-360	1b, 2b, 3b, 8h	9d	8m	5y	11dd	10c
II-361	1b, 2b, 3b, 8h	9d	8m	5y	11ee	10c
II-362	1b, 2b, 3b, 8h	9d	8m	5y	11ff	10c
II-363	1b, 2b, 3b, 8h	9d	8m	5y	11gg	10c
II-364	1b, 2b, 3b, 8h	9d	8q	5y	11a	10c
II-365	1b, 2b, 3b, 8h	9d	8q	5y	11b	10c
II-366	1b, 2b, 3b, 8h	9d	8q	5y	11c	10c
II-367	1b, 2b, 3b, 8h	9d	8q	5y	11d	10c
II-368	1b, 2b, 3b, 8h	9d	8q	5y	11e	10c
II-369	1b, 2b, 3b, 8h	9d	8q	5y	11f	10c
II-370	1b, 2b, 3b, 8h	9d	8q	5y	11g	10c
II-371	1b, 2b, 3b, 8h	9d	8q	5y	11h	10c
II-372	1b, 2b, 3b, 8h	9d	8q	5y	11i	10c
II-373	1b, 2b, 3b, 8h	9d	8q	5y	11j	10c
II-374	1b, 2b, 3b, 8h	9d	8q	5y	11k	10c
II-375	1b, 2b, 3b, 8h	9d	8q	5y	11l	10c
II-376	1b, 2b, 3b, 8h	9d	8q	5y	11m	10c
II-377	1b, 2b, 3b, 8h	9d	8q	5y	11n	10c
II-378	1b, 2b, 3b, 8h	9d	8q	5y	11o	10c
II-379	1b, 2b, 3b, 8h	9d	8q	5y	11p	10c
II-380	1b, 2b, 3b, 8h	9d	8q	5y	11q	10c
II-381	1b, 2b, 3b, 8h	9d	8q	5y	11r	10c
II-382	1b, 2b, 3b, 8h	9d	8q	5y	11s	10c
II-383	1b, 2b, 3b, 8h	9d	8q	5y	11t	10c
II-384	1b, 2b, 3b, 8h	9d	8q	5y	11u	10c
II-385	1b, 2b, 3b, 8h	9d	8q	5y	11v	10c
II-386	1b, 2b, 3b, 8h	9d	8q	5y	11w	10c
II-387	1b, 2b, 3b, 8h	9d	8q	5y	11x	10c
II-388	1b, 2b, 3b, 8h	9d	8q	5y	11y	10c
II-389	1b, 2b, 3b, 8h	9d	8q	5y	11z	10c
II-390	1b, 2b, 3b, 8h	9d	8q	5y	11aa	10c
II-391	1b, 2b, 3b, 8h	9d	8q	5y	11bb	10c
II-392	1b, 2b, 3b, 8h	9d	8q	5y	11cc	10c
II-393	1b, 2b, 3b, 8h	9d	8q	5y	11dd	10c
II-394	1b, 2b, 3b, 8h	9d	8q	5y	11ee	10c
II-395	1b, 2b, 3b, 8h	9d	8q	5y	11ff	10c
II-396	1b, 2b, 3b, 8h	9d	8q	5y	11gg	10c
II-397	1e, 2e, 3e, 8k	9a	8m	5y	11a	10c
II-398	1e, 2e, 3e, 8k	9a	8m	5y	11b	10c
II-399	1e, 2e, 3e, 8k	9a	8m	5y	11c	10c
II-400	1e, 2e, 3e, 8k	9a	8m	5y	11d	10c
II-401	1e, 2e, 3e, 8k	9a	8m	5y	11e	10c
II-402	1e, 2e, 3e, 8k	9a	8m	5y	11f	10c
II-403	1e, 2e, 3e, 8k	9a	8m	5y	11g	10c
II-404	1e, 2e, 3e, 8k	9a	8m	5y	11h	10c
II-405	1e, 2e, 3e, 8k	9a	8m	5y	11i	10c
II-406	1e, 2e, 3e, 8k	9a	8m	5y	11j	10c
II-407	1e, 2e, 3e, 8k	9a	8m	5y	11k	10c
II-408	1e, 2e, 3e, 8k	9a	8m	5y	11l	10c
II-409	1e, 2e, 3e, 8k	9a	8m	5y	11m	10c
II-410	1e, 2e, 3e, 8k	9a	8m	5y	11n	10c
II-411	1e, 2e, 3e, 8k	9a	8m	5y	11o	10c
II-412	1e, 2e, 3e, 8k	9a	8m	5y	11p	10c
II-413	1e, 2e, 3e, 8k	9a	8m	5y	11q	10c
II-414	1e, 2e, 3e, 8k	9a	8m	5y	11r	10c
II-415	1e, 2e, 3e, 8k	9a	8m	5y	11s	10c
II-416	1e, 2e, 3e, 8k	9a	8m	5y	11t	10c
II-417	1e, 2e, 3e, 8k	9a	8m	5y	11u	10c
II-418	1e, 2e, 3e, 8k	9a	8m	5y	11v	10c
II-419	1e, 2e, 3e, 8k	9a	8m	5y	11w	10c
II-420	1e, 2e, 3e, 8k	9a	8m	5y	11x	10c
II-421	1e, 2e, 3e, 8k	9a	8m	5y	11y	10c
II-422	1e, 2e, 3e, 8k	9a	8m	5y	11z	10c
II-423	1e, 2e, 3e, 8k	9a	8m	5y	11aa	10c
II-424	1e, 2e, 3e, 8k	9a	8m	5y	11bb	10c
II-425	1e, 2e, 3e, 8k	9a	8m	5y	11cc	10c
II-426	1e, 2e, 3e, 8k	9a	8m	5y	11dd	10c
II-427	1e, 2e, 3e, 8k	9a	8m	5y	11ee	10c
II-428	1e, 2e, 3e, 8k	9a	8m	5y	11ff	10c
II-429	1e, 2e, 3e, 8k	9a	8m	5y	11gg	10c
II-430	1e, 2e, 3e, 8k	9a	8q	5y	11a	10c
II-431	1e, 2e, 3e, 8k	9a	8q	5y	11b	10c
II-432	1e, 2e, 3e, 8k	9a	8q	5y	11c	10c
II-433	1e, 2e, 3e, 8k	9a	8q	5y	11d	10c
II-434	1e, 2e, 3e, 8k	9a	8q	5y	11e	10c
II-435	1e, 2e, 3e, 8k	9a	8q	5y	11f	10c
II-436	1e, 2e, 3e, 8k	9a	8q	5y	11g	10c
II-437	1e, 2e, 3e, 8k	9a	8q	5y	11h	10c
II-438	1e, 2e, 3e, 8k	9a	8q	5y	11i	10c
II-439	1e, 2e, 3e, 8k	9a	8q	5y	11j	10c
II-440	1e, 2e, 3e, 8k	9a	8q	5y	11k	10c
II-441	1e, 2e, 3e, 8k	9a	8q	5y	11l	10c
II-442	1e, 2e, 3e, 8k	9a	8q	5y	11m	10c
II-443	1e, 2e, 3e, 8k	9a	8q	5y	11n	10c
II-444	1e, 2e, 3e, 8k	9a	8q	5y	11o	10c
II-445	1e, 2e, 3e, 8k	9a	8q	5y	11p	10c
II-446	1e, 2e, 3e, 8k	9a	8q	5y	11q	10c
II-447	1e, 2e, 3e, 8k	9a	8q	5y	11r	10c
II-448	1e, 2e, 3e, 8k	9a	8q	5y	11s	10c
II-449	1e, 2e, 3e, 8k	9a	8q	5y	11t	10c
II-450	1e, 2e, 3e, 8k	9a	8q	5y	11u	10c
II-451	1e, 2e, 3e, 8k	9a	8q	5y	11v	10c
II-452	1e, 2e, 3e, 8k	9a	8q	5y	11w	10c
II-453	1e, 2e, 3e, 8k	9a	8q	5y	11x	10c
II-454	1e, 2e, 3e, 8k	9a	8q	5y	11y	10c
II-455	1e, 2e, 3e, 8k	9a	8q	5y	11z	10c
II-456	1e, 2e, 3e, 8k	9a	8q	5y	11aa	10c
II-457	1e, 2e, 3e, 8k	9a	8q	5y	11bb	10c
II-458	1e, 2e, 3e, 8k	9a	8q	5y	11cc	10c
II-459	1e, 2e, 3e, 8k	9a	8q	5y	11dd	10c
II-460	1e, 2e, 3e, 8k	9a	8q	5y	11ee	10c
II-461	1e, 2e, 3e, 8k	9a	8q	5y	11ff	10c
II-462	1e, 2e, 3e, 8k	9a	8q	5y	11gg	10c
II-463	1e, 2e, 3e, 8k	9d	8m	5y	11a	10c
II-464	1e, 2e, 3e, 8k	9d	8m	5y	11b	10c
II-465	1e, 2e, 3e, 8k	9d	8m	5y	11c	10c
II-466	1e, 2e, 3e, 8k	9d	8m	5y	11d	10c
II-467	1e, 2e, 3e, 8k	9d	8m	5y	11e	10c
II-468	1e, 2e, 3e, 8k	9d	8m	5y	11f	10c
II-469	1e, 2e, 3e, 8k	9d	8m	5y	11g	10c
II-470	1e, 2e, 3e, 8k	9d	8m	5y	11h	10c
II-471	1e, 2e, 3e, 8k	9d	8m	5y	11i	10c
II-472	1e, 2e, 3e, 8k	9d	8m	5y	11j	10c
II-473	1e, 2e, 3e, 8k	9d	8m	5y	11k	10c
II-474	1e, 2e, 3e, 8k	9d	8m	5y	11l	10c
II-475	1e, 2e, 3e, 8k	9d	8m	5y	11m	10c
II-476	1e, 2e, 3e, 8k	9d	8m	5y	11n	10c
II-477	1e, 2e, 3e, 8k	9d	8m	5y	11o	10c
II-478	1e, 2e, 3e, 8k	9d	8m	5y	11p	10c
II-479	1e, 2e, 3e, 8k	9d	8m	5y	11q	10c
II-480	1e, 2e, 3e, 8k	9d	8m	5y	11r	10c
II-481	1e, 2e, 3e, 8k	9d	8m	5y	11s	10c
II-482	1e, 2e, 3e, 8k	9d	8m	5y	11t	10c
II-483	1e, 2e, 3e, 8k	9d	8m	5y	11u	10c
II-484	1e, 2e, 3e, 8k	9d	8m	5y	11v	10c
II-485	1e, 2e, 3e, 8k	9d	8m	5y	11w	10c
II-486	1e, 2e, 3e, 8k	9d	8m	5y	11x	10c
II-487	1e, 2e, 3e, 8k	9d	8m	5y	11y	10c
II-488	1e, 2e, 3e, 8k	9d	8m	5y	11z	10c
II-489	1e, 2e, 3e, 8k	9d	8m	5y	11aa	10c
II-490	1e, 2e, 3e, 8k	9d	8m	5y	11bb	10c
II-491	1e, 2e, 3e, 8k	9d	8m	5y	11cc	10c
II-492	1e, 2e, 3e, 8k	9d	8m	5y	11dd	10c
II-493	1e, 2e, 3e, 8k	9d	8m	5y	11ee	10c
II-494	1e, 2e, 3e, 8k	9d	8m	5y	11ff	10c
II-495	1e, 2e, 3e, 8k	9d	8m	5y	11gg	10c
II-496	1e, 2e, 3e, 8k	9d	8q	5y	11a	10c
II-497	1e, 2e, 3e, 8k	9d	8q	5y	11b	10c
II-498	1e, 2e, 3e, 8k	9d	8q	5y	11c	10c
II-499	1e, 2e, 3e, 8k	9d	8q	5y	11d	10c
II-500	1e, 2e, 3e, 8k	9d	8q	5y	11e	10c
II-501	1e, 2e, 3e, 8k	9d	8q	5y	11f	10c
II-502	1e, 2e, 3e, 8k	9d	8q	5y	11g	10c
II-503	1e, 2e, 3e, 8k	9d	8q	5y	11h	10c
II-504	1e, 2e, 3e, 8k	9d	8q	5y	11i	10c
II-505	1e, 2e, 3e, 8k	9d	8q	5y	11j	10c
II-506	1e, 2e, 3e, 8k	9d	8q	5y	11k	10c
II-507	1e, 2e, 3e, 8k	9d	8q	5y	11l	10c
II-508	1e, 2e, 3e, 8k	9d	8q	5y	11m	10c
II-509	1e, 2e, 3e, 8k	9d	8q	5y	11n	10c
II-510	1e, 2e, 3e, 8k	9d	8q	5y	11o	10c
II-511	1e, 2e, 3e, 8k	9d	8q	5y	11p	10c
II-512	1e, 2e, 3e, 8k	9d	8q	5y	11q	10c
II-513	1e, 2e, 3e, 8k	9d	8q	5y	11r	10c
II-514	1e, 2e, 3e, 8k	9d	8q	5y	11s	10c
II-515	1e, 2e, 3e, 8k	9d	8q	5y	11t	10c
II-516	1e, 2e, 3e, 8k	9d	8q	5y	11u	10c
II-517	1e, 2e, 3e, 8k	9d	8q	5y	11v	10c
II-518	1e, 2e, 3e, 8k	9d	8q	5y	11w	10c
II-519	1e, 2e, 3e, 8k	9d	8q	5y	11x	10c
II-520	1e, 2e, 3e, 8k	9d	8q	5y	11y	10c
II-521	1e, 2e, 3e, 8k	9d	8q	5y	11z	10c
II-522	1e, 2e, 3e, 8k	9d	8q	5y	11aa	10c
II-523	1e, 2e, 3e, 8k	9d	8q	5y	11bb	10c
II-524	1e, 2e, 3e, 8k	9d	8q	5y	11cc	10c
II-525	1e, 2e, 3e, 8k	9d	8q	5y	11dd	10c
II-526	1e, 2e, 3e, 8k	9d	8q	5y	11ee	10c
II-527	1e, 2e, 3e, 8k	9d	8q	5y	11ff	10c
II-528	1e, 2e, 3e, 8k	9d	8q	5y	11gg	10c

In embodiment (3) of the first aspect, the invention comprises the compound of formula (III), or any one of (IIIa)-(IIIe),
and pharmaceutically acceptable salts thereof, wherein p is 0 or 1; R²⁰is —C₁-C₇alkyl-R⁹, -aryl-R⁹, aryl(C₁-C₇)alkyl-R⁹, or -heteroaryl-R⁹, and R³, R⁵, R⁶, R⁹, R³¹, L¹, X and Y are as defined for formula (I).
The invention further comprises subgenera of embodiment (3) of the first aspect in which the substituents are selected as any and all combinations of R³, R⁵, R⁶, R²⁰, R³¹, L¹, X, and Y as defined herein, including without limitation, the following:
each R³is independently one of groups (9a)-(9e) as defined above for formula (II).
R⁵is one of groups (8h)-(8l) as defined above for formula (I).
each R⁶is independently one of groups (8m)-(8q) as defined above for forniula. (I).
R²⁰is one of groups (11a)-(1 1 gg) as defined above for formula (II).
R³¹is one of groups (10a)-(10e) as defined above for formula (II).
L¹is one of groups (5v)-(5z) as defined above for formula (I).
X and Y are one of groups (7a)-(7g) as defined above for formula (I).
Particular embodiments of this embodiment of the invention include compounds of any one of formulae (III) and (IlIa)-(IIIe) wherein are defined in each of the following rows, wherein each entry is a group number as defined above:


Embodiment	R³& R⁵	R⁶	R²⁰	R³¹	L¹

III-1	9a, 8h	8m	11a	10c	5v
III-2	9a, 8h	8m	11b	10c	5v
III-3	9a, 8h	8m	11c	10c	5v
III-4	9a, 8h	8m	11d	10c	5v
III-5	9a, 8h	8m	11e	10c	5v
III-6	9a, 8h	8m	11f	10c	5v
III-7	9a, 8h	8m	11g	10c	5v
III-8	9a, 8h	8m	11h	10c	5v
III-9	9a, 8h	8m	11i	10c	5v
III-10	9a, 8h	8m	11j	10c	5v
III-11	9a, 8h	8m	11k	10c	5v
III-12	9a, 8h	8m	11l	10c	5v
III-13	9a, 8h	8m	11m	10c	5v
III-14	9a, 8h	8m	11n	10c	5v
III-15	9a, 8h	8m	11o	10c	5v
III-16	9a, 8h	8m	11p	10c	5v
III-17	9a, 8h	8m	11q	10c	5v
III-18	9a, 8h	8m	11r	10c	5v
III-19	9a, 8h	8m	11s	10c	5v
III-20	9a, 8h	8m	11t	10c	5v
III-21	9a, 8h	8m	11u	10c	5v
III-22	9a, 8h	8m	11v	10c	5v
III-23	9a, 8h	8m	11w	10c	5v
III-24	9a, 8h	8m	11x	10c	5v
III-25	9a, 8h	8m	11y	10c	5v
III-26	9a, 8h	8m	11z	10c	5v
III-27	9a, 8h	8m	11aa	10c	5v
III-28	9a, 8h	8m	11bb	10c	5v
III-29	9a, 8h	8m	11cc	10c	5v
III-30	9a, 8h	8m	11dd	10c	5v
III-31	9a, 8h	8m	11ee	10c	5v
III-32	9a, 8h	8m	11ff	10c	5v
III-33	9a, 8h	8m	11gg	10c	5v
III-34	9a, 8h	8q	11a	10c	5v
III-35	9a, 8h	8q	11b	10c	5v
III-36	9a, 8h	8q	11c	10c	5v
III-37	9a, 8h	8q	11d	10c	5v
III-38	9a, 8h	8q	11e	10c	5v
III-39	9a, 8h	8q	11f	10c	5v
III-40	9a, 8h	8q	11g	10c	5v
III-41	9a, 8h	8q	11h	10c	5v
III-42	9a, 8h	8q	11i	10c	5v
III-43	9a, 8h	8q	11j	10c	5v
III-44	9a, 8h	8q	11k	10c	5v
III-45	9a, 8h	8q	11l	10c	5v
III-46	9a, 8h	8q	11m	10c	5v
III-47	9a, 8h	8q	11n	10c	5v
III-48	9a, 8h	8q	11o	10c	5v
III-49	9a, 8h	8q	11p	10c	5v
III-50	9a, 8h	8q	11q	10c	5v
III-51	9a, 8h	8q	11r	10c	5v
III-52	9a, 8h	8q	11s	10c	5v
III-53	9a, 8h	8q	11t	10c	5v
III-54	9a, 8h	8q	11u	10c	5v
III-55	9a, 8h	8q	11v	10c	5v
III-56	9a, 8h	8q	11w	10c	5v
III-57	9a, 8h	8q	11x	10c	5v
III-58	9a, 8h	8q	11y	10c	5v
III-59	9a, 8h	8q	11z	10c	5v
III-60	9a, 8h	8q	11aa	10c	5v
III-61	9a, 8h	8q	11bb	10c	5v
III-62	9a, 8h	8q	11cc	10c	5v
III-63	9a, 8h	8q	11dd	10c	5v
III-64	9a, 8h	8q	11ee	10c	5v
III-65	9a, 8h	8q	11ff	10c	5v
III-66	9a, 8h	8q	11gg	10c	5v
III-67	9d, 8k	8m	11a	10c	5v
III-68	9d, 8k	8m	11b	10c	5v
III-69	9d, 8k	8m	11c	10c	5v
III-70	9d, 8k	8m	11d	10c	5v
III-71	9d, 8k	8m	11e	10c	5v
III-72	9d, 8k	8m	11f	10c	5v
III-73	9d, 8k	8m	11g	10c	5v
III-74	9d, 8k	8m	11h	10c	5v
III-75	9d, 8k	8m	11i	10c	5v
III-76	9d, 8k	8m	11j	10c	5v
III-77	9d, 8k	8m	11k	10c	5v
III-78	9d, 8k	8m	11l	10c	5v
III-79	9d, 8k	8m	11m	10c	5v
III-80	9d, 8k	8m	11n	10c	5v
III-81	9d, 8k	8m	11o	10c	5v
III-82	9d, 8k	8m	11p	10c	5v
III-83	9d, 8k	8m	11q	10c	5v
III-84	9d, 8k	8m	11r	10c	5v
III-85	9d, 8k	8m	11s	10c	5v
III-86	9d, 8k	8m	11t	10c	5v
III-87	9d, 8k	8m	11u	10c	5v
III-88	9d, 8k	8m	11v	10c	5v
III-89	9d, 8k	8m	11w	10c	5v
III-90	9d, 8k	8m	11x	10c	5v
III-91	9d, 8k	8m	11y	10c	5v
III-92	9d, 8k	8m	11z	10c	5v
III-93	9d, 8k	8m	11aa	10c	5v
III-94	9d, 8k	8m	11bb	10c	5v
III-95	9d, 8k	8m	11cc	10c	5v
III-96	9d, 8k	8m	11dd	10c	5v
III-97	9d, 8k	8m	11ee	10c	5v
III-98	9d, 8k	8m	11ff	10c	5v
III-99	9d, 8k	8m	11gg	10c	5v
III-100	9d, 8k	8q	11a	10c	5v
III-101	9d, 8k	8q	11b	10c	5v
III-102	9d, 8k	8q	11c	10c	5v
III-103	9d, 8k	8q	11d	10c	5v
III-104	9d, 8k	8q	11e	10c	5v
III-105	9d, 8k	8q	11f	10c	5v
III-106	9d, 8k	8q	11g	10c	5v
III-107	9d, 8k	8q	11h	10c	5v
III-108	9d, 8k	8q	11i	10c	5v
III-109	9d, 8k	8q	11j	10c	5v
III-110	9d, 8k	8q	11k	10c	5v
III-111	9d, 8k	8q	11l	10c	5v
III-112	9d, 8k	8q	11m	10c	5v
III-113	9d, 8k	8q	11n	10c	5v
III-114	9d, 8k	8q	11o	10c	5v
III-115	9d, 8k	8q	11p	10c	5v
III-116	9d, 8k	8q	11q	10c	5v
III-117	9d, 8k	8q	11r	10c	5v
III-118	9d, 8k	8q	11s	10c	5v
III-119	9d, 8k	8q	11t	10c	5v
III-120	9d, 8k	8q	11u	10c	5v
III-121	9d, 8k	8q	11v	10c	5v
III-122	9d, 8k	8q	11w	10c	5v
III-123	9d, 8k	8q	11x	10c	5v
III-124	9d, 8k	8q	11y	10c	5v
III-125	9d, 8k	8q	11z	10c	5v
III-126	9d, 8k	8q	11aa	10c	5v
III-127	9d, 8k	8q	11bb	10c	5v
III-128	9d, 8k	8q	11cc	10c	5v
III-129	9d, 8k	8q	11dd	10c	5v
III-130	9d, 8k	8q	11ee	10c	5v
III-131	9d, 8k	8q	11ff	10c	5v
III-132	9d, 8k	8q	11gg	10c	5v
III-133	9a, 8h	8m	11a	10c	5y
III-134	9a, 8h	8m	11b	10c	5y
III-135	9a, 8h	8m	11c	10c	5y
III-136	9a, 8h	8m	11d	10c	5y
III-137	9a, 8h	8m	11e	10c	5y
III-138	9a, 8h	8m	11f	10c	5y
III-139	9a, 8h	8m	11g	10c	5y
III-140	9a, 8h	8m	11h	10c	5y
III-141	9a, 8h	8m	11i	10c	5y
III-142	9a, 8h	8m	11j	10c	5y
III-143	9a, 8h	8m	11k	10c	5y
III-144	9a, 8h	8m	11l	10c	5y
III-145	9a, 8h	8m	11m	10c	5y
III-146	9a, 8h	8m	11n	10c	5y
III-147	9a, 8h	8m	11o	10c	5y
III-148	9a, 8h	8m	11p	10c	5y
III-149	9a, 8h	8m	11q	10c	5y
III-150	9a, 8h	8m	11r	10c	5y
III-151	9a, 8h	8m	11s	10c	5y
III-152	9a, 8h	8m	11t	10c	5y
III-153	9a, 8h	8m	11u	10c	5y
III-154	9a, 8h	8m	11v	10c	5y
III-155	9a, 8h	8m	11w	10c	5y
III-156	9a, 8h	8m	11x	10c	5y
III-157	9a, 8h	8m	11y	10c	5y
III-158	9a, 8h	8m	11z	10c	5y
III-159	9a, 8h	8m	11aa	10c	5y
III-160	9a, 8h	8m	11bb	10c	5y
III-161	9a, 8h	8m	11cc	10c	5y
III-162	9a, 8h	8m	1dd	10c	5y
III-163	9a, 8h	8m	11ee	10c	5y
III-164	9a, 8h	8m	11ff	10c	5y
III-165	9a, 8h	8m	11gg	10c	5y
III-166	9a, 8h	8q	11a	10c	5y
III-167	9a, 8h	8q	11b	10c	5y
III-168	9a, 8h	8q	11c	10c	5y
III-169	9a, 8h	8q	11d	10c	5y
III-170	9a, 8h	8q	11e	10c	5y
III-171	9a, 8h	8q	11f	10c	5y
III-172	9a, 8h	8q	11g	10c	5y
III-173	9a, 8h	8q	11h	10c	5y
III-174	9a, 8h	8q	11i	10c	5y
III-175	9a, 8h	8q	11j	10c	5y
III-176	9a, 8h	8q	11k	10c	5y
III-177	9a, 8h	8q	11l	10c	5y
III-178	9a, 8h	8q	11m	10c	5y
III-179	9a, 8h	8q	11n	10c	5y
III-180	9a, 8h	8q	11o	10c	5y
III-181	9a, 8h	8q	11p	10c	5y
III-182	9a, 8h	8q	11q	10c	5y
III-183	9a, 8h	8q	11r	10c	5y
III-184	9a, 8h	8q	11s	10c	5y
III-185	9a, 8h	8q	11t	10c	5y
III-186	9a, 8h	8q	11u	10c	5y
III-187	9a, 8h	8q	11v	10c	5y
III-188	9a, 8h	8q	11w	10c	5y
III-189	9a, 8h	8q	11x	10c	5y
III-190	9a, 8h	8q	11y	10c	5y
III-191	9a, 8h	8q	11z	10c	5y
III-192	9a, 8h	8q	11aa	10c	5y
III-193	9a, 8h	8q	11bb	10c	5y
III-194	9a, 8h	8q	11cc	10c	5y
III-195	9a, 8h	8q	11dd	10c	5y
III-196	9a, 8h	8q	11ee	10c	5y
III-197	9a, 8h	8q	11ff	10c	5y
III-198	9a, 8h	8q	11gg	10c	5y
III-199	9d, 8k	8m	11a	10c	5y
III-200	9d, 8k	8m	11b	10c	5y
III-201	9d, 8k	8m	11c	10c	5y
III-202	9d, 8k	8m	11d	10c	5y
III-203	9d, 8k	8m	11e	10c	5y
III-204	9d, 8k	8m	11f	10c	5y
III-205	9d, 8k	8m	11g	10c	5y
III-206	9d, 8k	8m	11h	10c	5y
III-207	9d, 8k	8m	11i	10c	5y
III-208	9d, 8k	8m	11j	10c	5y
III-209	9d, 8k	8m	11k	10c	5y
III-210	9d, 8k	8m	11l	10c	5y
III-211	9d, 8k	8m	11m	10c	5y
III-212	9d, 8k	8m	11n	10c	5y
III-213	9d, 8k	8m	11o	10c	5y
III-214	9d, 8k	8m	11p	10c	5y
III-215	9d, 8k	8m	11q	10c	5y
III-216	9d, 8k	8m	11r	10c	5y
III-217	9d, 8k	8m	11s	10c	5y
III-218	9d, 8k	8m	11t	10c	5y
III-219	9d, 8k	8m	11u	10c	5y
III-220	9d, 8k	8m	11v	10c	5y
III-221	9d, 8k	8m	11w	10c	5y
III-222	9d, 8k	8m	11x	10c	5y
III-223	9d, 8k	8m	11y	10c	5y
III-224	9d, 8k	8m	11z	10c	5y
III-225	9d, 8k	8m	11aa	10c	5y
III-226	9d, 8k	8m	11bb	10c	5y
III-227	9d, 8k	8m	11cc	10c	5y
III-228	9d, 8k	8m	11dd	10c	5y
III-229	9d, 8k	8m	11ee	10c	5y
III-230	9d, 8k	8m	11ff	10c	5y
III-231	9d, 8k	8m	11gg	10c	5y
III-232	9d, 8k	8q	11a	10c	5y
III-233	9d, 8k	8q	11b	10c	5y
III-234	9d, 8k	8q	11c	10c	5y
III-235	9d, 8k	8q	11d	10c	5y
III-236	9d, 8k	8q	11e	10c	5y
III-237	9d, 8k	8q	11f	10c	5y
III-238	9d, 8k	8q	11g	10c	5y
III-239	9d, 8k	8q	11h	10c	5y
III-240	9d, 8k	8q	11i	10c	5y
III-241	9d, 8k	8q	11j	10c	5y
III-242	9d, 8k	8q	11k	10c	5y
III-243	9d, 8k	8q	11l	10c	5y
III-244	9d, 8k	8q	11m	10c	5y
III-245	9d, 8k	8q	11n	10c	5y
III-246	9d, 8k	8q	11o	10c	5y
III-247	9d, 8k	8q	11p	10c	5y
III-248	9d, 8k	8q	11q	10c	5y
III-249	9d, 8k	8q	11r	10c	5y
III-250	9d, 8k	8q	11s	10c	5y
III-251	9d, 8k	8q	11t	10c	5y
III-252	9d, 8k	8q	11u	10c	5y
III-253	9d, 8k	8q	11v	10c	5y
III-254	9d, 8k	8q	11w	10c	5y
III-255	9d, 8k	8q	11x	10c	5y
III-256	9d, 8k	8q	11y	10c	5y
III-257	9d, 8k	8q	11z	10c	5y
III-258	9d, 8k	8q	11aa	10c	5y
III-259	9d, 8k	8q	11bb	10c	5y
III-260	9d, 8k	8q	11cc	10c	5y
III-261	9d, 8k	8q	11dd	10c	5y
III-262	9d, 8k	8q	11ee	10c	5y
III-263	9d, 8k	8q	11ff	10c	5y
III-264	9d, 8k	8q	11gg	10c	5y

In embodiment (4) of the first aspect, the invention comprises the compound of formula (IV), or any one of (IVa)-(IVe),
and pharmaceutically acceptable salts thereof, wherein R²⁰is —C₁-C₇alkyl-R⁹, -aryl-R⁹, -aryl(C₁-C₇)alkyl-R⁹, or -heteroaryl-R⁹, and R³, R⁵, R⁶, L^I, and R⁹are as defined for formula (I).
The invention further comprises subgenera of embodiment (4) of the first aspect in which the substituents are selected as anvand all combinations of R³, R⁵, R⁶, R²⁰, L¹, X, and Y as defined herein, including without limitation,
each R³is independently one of groups (9a)-(9e) as defined above for formula (II).
R⁵is one of groups (8h)-(8l) as defined above for formula (I).
each R⁶is independently one of groups (8m)-(8q) as defined above for formula (I).
L¹is one of groups (5v)-(5z) as defined above for formula (I).
X and Y are one of groups (7a)-(7g) as defined above for formula (I).
R²⁰is one of groups (11a)-(11gg) as defined above for formula (II).
Particular embodiments of this embodiment of the invention include compounds of any one of formulae (IV) and (IVa)-(IVe) wherein are defined in each of the following rows, wherein each entry is a group number as defined above:


Embodiment	R³& R⁵	R⁶	R²⁰	L¹

IV-1	9a, 8h	8m	11a	5v
IV-2	9a, 8h	8m	11b	5v
IV-3	9a, 8h	8m	11c	5v
IV-4	9a, 8h	8m	11d	5v
IV-5	9a, 8h	8m	11e	5v
IV-6	9a, 8h	8m	11f	5v
IV-7	9a, 8h	8m	11g	5v
IV-8	9a, 8h	8m	11h	5v
IV-9	9a, 8h	8m	11i	5v
IV-10	9a, 8h	8m	11j	5v
IV-11	9a, 8h	8m	11k	5v
IV-12	9a, 8h	8m	11l	5v
IV-13	9a, 8h	8m	11m	5v
IV-14	9a, 8h	8m	11n	5v
IV-15	9a, 8h	8m	11o	5v
IV-16	9a, 8h	8m	11p	5v
IV-17	9a, 8h	8m	11q	5v
IV-18	9a, 8h	8m	11r	5v
IV-19	9a, 8h	8m	11s	5v
IV-20	9a, 8h	8m	11t	5v
IV-21	9a, 8h	8m	11u	5v
IV-22	9a, 8h	8m	11v	5v
IV-23	9a, 8h	8m	11w	5v
IV-24	9a, 8h	8m	11x	5v
IV-25	9a, 8h	8m	11y	5v
IV-26	9a, 8h	8m	11z	5v
IV-27	9a, 8h	8m	11aa	5v
IV-28	9a, 8h	8m	11bb	5v
IV-29	9a, 8h	8m	11cc	5v
IV-30	9a, 8h	8m	11dd	5v
IV-31	9a, 8h	8m	11ee	5v
IV-32	9a, 8h	8m	11ff	5v
IV-33	9a, 8h	8m	11gg	5v
IV-34	9a, 8h	8q	11a	5v
IV-35	9a, 8h	8q	11b	5v
IV-36	9a, 8h	8q	11c	5v
IV-37	9a, 8h	8q	11d	5v
IV-38	9a, 8h	8q	11e	5v
IV-39	9a, 8h	8q	11f	5v
IV-40	9a, 8h	8q	11g	5v
IV-41	9a, 8h	8q	11h	5v
IV-42	9a, 8h	8q	11i	5v
IV-43	9a, 8h	8q	11j	5v
IV-44	9a, 8h	8q	11k	5v
IV-45	9a, 8h	8q	11l	5v
IV-46	9a, 8h	8q	11m	5v
IV-47	9a, 8h	8q	11n	5v
IV-48	9a, 8h	8q	11o	5v
IV-49	9a, 8h	8q	11p	5v
IV-50	9a, 8h	8q	11q	5v
IV-51	9a, 8h	8q	11r	5v
IV-52	9a, 8h	8q	11s	5v
IV-53	9a, 8h	8q	11t	5v
IV-54	9a, 8h	8q	11u	5v
IV-55	9a, 8h	8q	11v	5v
IV-56	9a, 8h	8q	11w	5v
IV-57	9a, 8h	8q	11x	5v
IV-58	9a, 8h	8q	11y	5v
IV-59	9a, 8h	8q	11z	5v
IV-60	9a, 8h	8q	11aa	5v
IV-61	9a, 8h	8q	11bb	5v
IV-62	9a, 8h	8q	11cc	5v
IV-63	9a, 8h	8q	11dd	5v
IV-64	9a, 8h	8q	11ee	5v
IV-65	9a, 8h	8q	11ff	5v
IV-66	9a, 8h	8q	11gg	5v
IV-67	9d, 8k	8m	11a	5v
IV-68	9d, 8k	8m	11b	5v
IV-69	9d, 8k	8m	11c	5v
IV-70	9d, 8k	8m	11d	5v
IV-71	9d, 8k	8m	11e	5v
IV-72	9d, 8k	8m	11f	5v
IV-73	9d, 8k	8m	11g	5v
IV-74	9d, 8k	8m	11h	5v
IV-75	9d, 8k	8m	11i	5v
IV-76	9d, 8k	8m	11j	5v
IV-77	9d, 8k	8m	11k	5v
IV-78	9d, 8k	8m	11l	5v
IV-79	9d, 8k	8m	11m	5v
IV-80	9d, 8k	8m	11n	5v
IV-81	9d, 8k	8m	11o	5v
IV-82	9d, 8k	8m	11p	5v
IV-83	9d, 8k	8m	11q	5v
IV-84	9d, 8k	8m	11r	5v
IV-85	9d, 8k	8m	11s	5v
IV-86	9d, 8k	8m	11t	5v
IV-87	9d, 8k	8m	11u	5v
IV-88	9d, 8k	8m	11v	5v
IV-89	9d, 8k	8m	11w	5v
IV-90	9d, 8k	8m	11x	5v
IV-91	9d, 8k	8m	11y	5v
IV-92	9d, 8k	8m	11z	5v
IV-93	9d, 8k	8m	11aa	5v
IV-94	9d, 8k	8m	11bb	5v
IV-95	9d, 8k	8m	11cc	5v
IV-96	9d, 8k	8m	11dd	5v
IV-97	9d, 8k	8m	11ee	5v
IV-98	9d, 8k	8m	11ff	5v
IV-99	9d, 8k	8m	11gg	5v
IV-100	9d, 8k	8q	11a	5v
IV-101	9d, 8k	8q	11b	5v
IV-102	9d, 8k	8q	11c	5v
IV-103	9d, 8k	8q	11d	5v
IV-104	9d, 8k	8q	11e	5v
IV-105	9d, 8k	8q	11f	5v
IV-106	9d, 8k	8q	11g	5v
IV-107	9d, 8k	8q	11h	5v
IV-108	9d, 8k	8q	11i	5v
IV-109	9d, 8k	8q	11j	5v
IV-110	9d, 8k	8q	11k	5v
IV-111	9d, 8k	8q	11l	5v
IV-112	9d, 8k	8q	11m	5v
IV-113	9d, 8k	8q	11n	5v
IV-114	9d, 8k	8q	11o	5v
IV-115	9d, 8k	8q	11p	5v
IV-116	9d, 8k	8q	11q	5v
IV-117	9d, 8k	8q	11r	5v
IV-118	9d, 8k	8q	11s	5v
IV-119	9d, 8k	8q	11t	5v
IV-120	9d, 8k	8q	11u	5v
IV-121	9d, 8k	8q	11v	5v
IV-122	9d, 8k	8q	11w	5v
IV-123	9d, 8k	8q	11x	5v
IV-124	9d, 8k	8q	11y	5v
IV-125	9d, 8k	8q	11z	5v
IV-126	9d, 8k	8q	11aa	5v
IV-127	9d, 8k	8q	11bb	5v
IV-128	9d, 8k	8q	11cc	5v
IV-129	9d, 8k	8q	11dd	5v
IV-130	9d, 8k	8q	11ee	5v
IV-131	9d, 8k	8q	11ff	5v
IV-132	9d, 8k	8q	11gg	5v
IV-133	9a, 8h	8m	11a	5y
IV-134	9a, 8h	8m	11b	5y
IV-135	9a, 8h	8m	11c	5y
IV-136	9a, 8h	8m	11d	5y
IV-137	9a, 8h	8m	11e	5y
IV-138	9a, 8h	8m	11f	5y
IV-139	9a, 8h	8m	11g	5y
IV-140	9a, 8h	8m	11h	5y
IV-141	9a, 8h	8m	11i	5y
IV-142	9a, 8h	8m	11j	5y
IV-143	9a, 8h	8m	11k	5y
IV-144	9a, 8h	8m	11l	5y
IV-145	9a, 8h	8m	11m	5y
IV-146	9a, 8h	8m	11n	5y
IV-147	9a, 8h	8m	11o	5y
IV-148	9a, 8h	8m	11p	5y
IV-149	9a, 8h	8m	11q	5y
IV-150	9a, 8h	8m	11r	5y
IV-151	9a, 8h	8m	11s	5y
IV-152	9a, 8h	8m	11t	5y
IV-153	9a, 8h	8m	11u	5y
IV-154	9a, 8h	8m	11v	5y
IV-155	9a, 8h	8m	11w	5y
IV-156	9a, 8h	8m	11x	5y
IV-157	9a, 8h	8m	11y	5y
IV-158	9a, 8h	8m	11z	5y
IV-159	9a, 8h	8m	11aa	5y
IV-160	9a, 8h	8m	11bb	5y
IV-161	9a, 8h	8m	11cc	5y
IV-162	9a, 8h	8m	11dd	5y
IV-163	9a, 8h	8m	11ee	5y
IV-164	9a, 8h	8m	11ff	5y
IV-165	9a, 8h	8m	11gg	5y
IV-166	9a, 8h	8q	11a	5y
IV-167	9a, 8h	8q	11b	5y
IV-168	9a, 8h	8q	11c	5y
IV-169	9a, 8h	8q	11d	5y
IV-170	9a, 8h	8q	11e	5y
IV-171	9a, 8h	8q	11f	5y
IV-172	9a, 8h	8q	11g	5y
IV-173	9a, 8h	8q	11h	5y
IV-174	9a, 8h	8q	11i	5y
IV-175	9a, 8h	8q	11j	5y
IV-176	9a, 8h	8q	11k	5y
IV-177	9a, 8h	8q	11l	5y
IV-178	9a, 8h	8q	11m	5y
IV-179	9a, 8h	8q	11n	5y
IV-180	9a, 8h	8q	11o	5y
IV-181	9a, 8h	8q	11p	5y
IV-182	9a, 8h	8q	11q	5y
IV-183	9a, 8h	8q	11r	5y
IV-184	9a, 8h	8q	11s	5y
IV-185	9a, 8h	8q	11t	5y
IV-186	9a, 8h	8q	11u	5y
IV-187	9a, 8h	8q	11v	5y
IV-188	9a, 8h	8q	11w	5y
IV-189	9a, 8h	8q	11x	5y
IV-190	9a, 8h	8q	11y	5y
IV-191	9a, 8h	8q	11z	5y
IV-192	9a, 8h	8q	11aa	5y
IV-193	9a, 8h	8q	11bb	5y
IV-194	9a, 8h	8q	11cc	5y
IV-195	9a, 8h	8q	11dd	5y
IV-196	9a, 8h	8q	11ee	5y
IV-197	9a, 8h	8q	11ff	5y
IV-198	9a, 8h	8q	11gg	5y
IV-199	9d, 8k	8m	11a	5y
IV-200	9d, 8k	8m	11b	5y
IV-201	9d, 8k	8m	11e	5y
IV-202	9d, 8k	8m	11d	5y
IV-203	9d, 8k	8m	11e	5y
IV-204	9d, 8k	8m	11f	5y
IV-205	9d, 8k	8m	11g	5y
IV-206	9d, 8k	8m	11h	5y
IV-207	9d, 8k	8m	11i	5y
IV-208	9d, 8k	8m	11j	5y
IV-209	9d, 8k	8m	11k	5y
IV-210	9d, 8k	8m	11l	5y
IV-211	9d, 8k	8m	11m	5y
IV-212	9d, 8k	8m	11n	5y
IV-213	9d, 8k	8m	11o	5y
IV-214	9d, 8k	8m	11p	5y
IV-215	9d, 8k	8m	11q	5y
IV-216	9d, 8k	8m	11r	5y
IV-217	9d, 8k	8m	11s	5y
IV-218	9d, 8k	8m	11t	5y
IV-219	9d, 8k	8m	11u	5y
IV-220	9d, 8k	8m	11v	5y
IV-221	9d, 8k	8m	11w	5y
IV-222	9d, 8k	8m	11x	5y
IV-223	9d, 8k	8m	11y	5y
IV-224	9d, 8k	8m	11z	5y
IV-225	9d, 8k	8m	11aa	5y
IV-226	9d, 8k	8m	11bb	5y
IV-227	9d, 8k	8m	11cc	5y
IV-228	9d, 8k	8m	11dd	5y
IV-229	9d, 8k	8m	11ee	5y
IV-230	9d, 8k	8m	11ff	5y
IV-231	9d, 8k	8m	11gg	5y
IV-232	9d, 8k	8q	11a	5y
IV-233	9d, 8k	8q	11b	5y
IV-234	9d, 8k	8q	11c	5y
IV-235	9d, 8k	8q	11d	5y
IV-236	9d, 8k	8q	11e	5y
IV-237	9d, 8k	8q	11f	5y
IV-238	9d, 8k	8q	11g	5y
IV-239	9d, 8k	8q	11h	5y
IV-240	9d, 8k	8q	11i	5y
IV-241	9d, 8k	8q	11j	5y
IV-242	9d, 8k	8q	11k	5y
IV-243	9d, 8k	8q	11l	5y
IV-244	9d, 8k	8q	11m	5y
IV-245	9d, 8k	8q	11n	5y
IV-246	9d, 8k	8q	11o	5y
IV-247	9d, 8k	8q	11p	5y
IV-248	9d, 8k	8q	11q	5y
IV-249	9d, 8k	8q	11r	5y
IV-250	9d, 8k	8q	11s	5y
IV-251	9d, 8k	8q	11t	5y
IV-252	9d, 8k	8q	11u	5y
IV-253	9d, 8k	8q	11v	5y
IV-254	9d, 8k	8q	11w	5y
IV-255	9d, 8k	8q	11x	5y
IV-256	9d, 8k	8q	11y	5y
IV-257	9d, 8k	8q	11z	5y
IV-258	9d, 8k	8q	11aa	5y
IV-259	9d, 8k	8q	11bb	5y
IV-260	9d, 8k	8q	11cc	5y
IV-261	9d, 8k	8q	11dd	5y
IV-262	9d, 8k	8q	11ee	5y
IV-263	9d, 8k	8q	11ff	5y
IV-264	9d, 8k	8q	11gg	5y

Examples of a PSMA inhibitor bearing a polymer conjugate (PEG)
where n is 1-200, 100-200, 150-200, 1-100, 1-50, 1-10, or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
The invention compounds falling under the embodiments as disclosed above are not one or all of the following compounds in Table 1:

TABLE 1

	¹⁸F-S-2-((2-(S-4-(4-fluorobenzamido)- 4-carboxybutanamido)-S-2- carboxyethoxy)hydroxyphosphoryl- amino)-pentanedioic acid.







	N-{[(2S)-2-carboxy-2-({4-[({3-[(2- {[3-carboxy-4-(6-hydroxy-3-oxo- 9,9a-dihydro-3H-xanthen-9-yl) phenyl]amino}-2-oxoethyl)thio] propanoyl}amino)methyl]benzoyl} amino)ethoxy](hydroxy)phosphoryl}- L-glutamic acid;

	N-[{(2S)-2-carboxy-2-[(4-{[(6- {[3-carboxy-4-(6-hydroxy-3-oxo- 9,9a-dihydro-3H-xanthen-9-yl) benzoyl]amino}hexanoyl)amino] methyl}benzoyl)amino]ethoxy} (hydroxy)phosphoryl]-L-glutamic acid;

	N-{3-[(2-{[3-carboxy-4-(6-hydroxy- 3-oxo-9,9a-dihydro-3H-xanthen- 9-yl)phenyl]amino}-2-oxoethyl) thio]propanoyl}-L-γ-glutamyl-O- [{[(1S)-1,3-dicarboxy- propyl]amino}(hydroxy) phosphoryl]-L-serine;

	N-(6-{[3-carboxy-4-(6-hydroxy- 3-oxo-9,9a-dihydro-3H- xanthen-9-yl)benzoyl]amino}hexanoyl)- L-γ-glutamyl-O-[{[(1S)-1,3-dicarboxy- propyl]amino}(hydroxy)prosphoryl]- L-serine;

	N-[{(2S)-2-carboxy-2-[({[3- carboxy-4-(6-hydroxy-3- oxo-9,9a-dihydro-3H-xanthen- 9-yl)phenyl]amino}carbonothioyl) amino]ethoxy}(hydroxy)phosphoryl]- L-glutamic acid;

	N-{[(4-{2-[bis(carboxymethyl) amino]-3-[{2-[bis(carboxy- methyl)amino]ethyl}(carboxymethyl) amino]propyl}phenyl)amino] carbonothioyl}-L-γ-glutamyl-O- [{[(1S)-1,3-dicarboxypropyl]amino} (hydroxy)phosphoryl]-L-serine;

	N-{6-[(6-{[5-(2-oxohexahydro- 1H-thieno[3,4-d]imidazol-4- yl)pentanoyl]amino}hexanoyl)amino] hexanoyl}-L-γ-glutamyl-O-[{[(1S)- 1,3-dicarboxypropyl]amino} (hydroxy)phosphoryl]-L-serine;

	N-{[(2S)-2-carboxy-2-({4-[({6- [(6-{[5-(2-oxohexahydro-1H- thieno[3,4-d]imidazol-4- yl)pentanoyl]amino}hexanoyl)amino] hexanoyl}amino)methyl]benzoyl} amino)ethoxy](hydroxy)phosphoryl}- L-glutamic acid

In an embodiment , the invention comprises the compound of formula (V),
and pharmaceutically acceptable salts thereof, wherein R^AA, L¹, X, Y, R³, R⁵, R° , and R¹⁰are R^AAis hydrogen, C₁-C₇alkyl, aryl, heteroaryl, arylC₁-C₇alkyl, or heteroarylC₁-C₇alkyl, wherein the alkyl, arylalkyl, and heteroarylalkyl groups are optionally substituted with 1, 2, 3,4, or 5 R^A1groups, wherein each R^A1is independently —OR^A2, —N(R^A2)₂, —C(O)OR^A2, —C(O)N(R^A2)₂, —N(R^A2)C(═NR^A2)N(R^A2)₂, or C₁-C₇alkyl, wherein each R^A2is independently hydrogen or C₁-C₁alkyl.
L¹is one of groups (5u)-(5z) as defined above for formula (I).
X and Y are one of groups (7a)-(7g) as defined above for formula (I).
each R³is independently one of groups (9a)-(9e) as defined above for formula (II).
R⁵is one of groups (8h)-(8i) as defined above for formula (I).
each R⁶is independently one of groups (8m)-(8q) as defined above for formula (I).
R¹⁰is -aryl-R⁹, -heteroaryl-R⁹, —C₁-C₇alkyl-aryl-R⁹, —C₁-C₁alkyl-heteroaryl-R⁹, —C₁-C₇alkyl-R⁸, -aryl-C₁-C₇alkyl-R⁸, or -heteroaryl-C₁-C₇alkyl-R⁸, wherein

- - the aryl, heteroaryl, alkyl-aryl, aryl-alkyl, alkyl-heteroaryl, and heteroaryl-alkyl groups are optionally substituted with one, two, or three groups which are each independently halomethyl, dihalomethyl, trihalomethyl, —C(O)R¹¹, —CO(O)R¹², —C(O)N(R¹²)₂, wherein
    - each R¹¹is independently hydrogen, —C₁-C₇alkyl, —C₁-C₇alkylaryl, or —C₁-C₇alkylheteroaryl; and
    - each R¹²is independently R¹¹or a protecting group;

In an embodiment of any of the preceding embodiments of formulae (I)-(VI), (IIa)-(IIe), (IIIa)-(IIIe), (IVa)-(IVe), (Va)-(Vc), and (VIa)-(VII), R⁹can be one of groups (12a)-(12o):

- (12a) a detectable label, or a cytotoxic group.
- (12b) a detectable label.
- (12c) ¹⁸F.
- (12d) biotin.
- (12e) a cytotoxic group.
- (12f) —N₃, —C≡CH, —ONH₂, —C(O)N(H)NH₂, or —N(H)NH₂.
- (12g) —N₃or —C≡CH.
- (12h) —C≡CH,
- (12i) —N₃.
- (12j) a pendant group comprising either a detectable label, or a cytotoxic group.
- (12k) a pendant group comprising a detectable label.
- (12l) a pendant group comprising a cytotoxic group.
- (12m) a pendant group bonded to a solid support.

Suitable detectable labels include, but are not limited to, fluorescent or dichroic dyes; bonded radionuclides; radioisotopes coordinated to a chelating moiety, such as chelated ^99mTc, ⁶⁴Cu, ⁶⁸Ga, ¹¹¹In, or ¹⁵²Gd; chelated MRI contrast agents, such as Gd, Mn, Ba, superparamagnetic iron oxide (SIPO)(e.g., 300-3500 nm, or 60-150 nm diameter particles), ultrasmall superparamagnetic iron oxide (USPIO)(e.g., 10-30 mn diameter particles); and chelated radiotherapeutics, such as ¹⁷¹Lu or ⁹⁰Y.
Radionuclides useful within the present invention include gamma-emitters, positron-emitters, Auger electron-emitters, X-ray emitters and fluorescence-emitters, with beta- or alpha-emitters preferred for therapeutic use. Examples of useful radionuclides include: ¹⁸F, ³²P, ³³P, ⁴³K, ⁴⁷Sc, ⁵²Fe, ⁵⁷Co, ⁶⁴Cu, ⁶⁷Ga, ⁶⁷Cu, ⁶⁸Ga, ⁷¹Ge, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ⁷⁷As, ⁷⁷Br, ⁸¹Rb, ^81mKr, ^87mSr, ⁹⁰Y, ⁹⁷Ru, ^99mTc, ¹⁰⁰Rh, ¹⁰¹Rh, ¹⁰³Pb, ¹⁰⁵Rh, ¹⁰⁹Pd, ¹¹¹Ag, ¹¹¹In, ¹¹³In, ¹¹⁹Sb, ¹²¹Sb, ¹²³I, ¹²⁵I, ¹²⁷Cs, ¹²⁸Ba, ¹²⁹Cs, ¹³¹I, ¹³¹Cs, ¹⁴³Pr, ¹⁵³Sm, ¹⁶¹Tb, ¹⁶⁶Ho, ¹⁶⁹Eu, ¹⁷⁷In, ¹³⁶Re, ¹⁸⁸Re, ¹⁸⁹Re, ¹⁹¹Os, ¹⁹³Pt, ¹⁹⁴Ir, ¹⁹⁷Hg, ¹⁹⁹Au, ²⁰³Pb, ²¹¹At, ²¹²Pb, ²¹²Bi and ²¹³Bi.
In certain embodiments, the detectable label can be a bonded radionuclide. In one embodiment, the radionuclide is ¹⁸F, ¹²³I, ¹²⁴I, ¹²⁵, or ¹³¹I.
When R⁹is a radiotisotope, it can be coordinated to a chelating moiety, such as chelated ^99mTe, ⁶⁴Cu, ⁶⁸Ga, or ¹¹¹In. In certain embodiments, R⁹is ^99mTe coordinated to a chelating moiety. Moieties which can serve as chelating ligands, include, for example MAG 3 (mercaptoacetyltriglycine) or bispicolylamine (SAAC); derivatives of 1,4,7,10-tetraazacyclododecanetetraacetie acid (DOTA), ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA) and 1-p-Isothiocyanato-benzyl-methyl-diethylenetriaminepentaacetic acid (ITC-MX). These chelators typically have groups on the side chain by which the chelator can be used for attachment to a parent molecule. Such groups include, e.g., benzylisothiocyanate, by which the MAG 3, SAAC. DTPA, NOTA, CHX-A′ or EDTA can be coupled to, e.g., an amine group of the parent molecule.
In another embodiment, the ¹⁸F in the ¹⁸F-containing structures displayed hereinabove can be replaced with another radionuclide disclosed herein.
Suitable cytotoxic groups include, but are not limited to, chelated or bonded radiotherapeutics, photosensitizers, small molecule agents such as paclitaxel, camptothecin, and doxorubicin, as well as lysosomal disrupting agents, such as, ¹²⁵I, ¹³¹I, ¹⁷⁷Lu, ¹⁶⁸Rh, or ⁹⁰Y.
An example of a ¹⁸F-labeled peptide analog of CTT-54 which could be made is a pharmaceutically acceptable salt of,
Exemplary cold compounds which could be 18F labeled were examined using the assay described in U.S. Pat. No. 7,696,185 to Berkman which is herein incorporated by reference.
These results are consistent with those observed for the SFB-CTT-54 conjugate initially described in “Assessment of an ¹⁸F-labeled phosphoramidate peptidomimetic as a new prostate-specific membrane antigen-targeted imaging agent for prostate cancer”. Lapi, S. E., et al., J. Nucl. Med. 2009, 50(12), 2042-8, which is hereby incorporated by reference in its entirety. The heteroatomic ring (nicotinamide) did not diminish the PSMA binding observed for the SFB-CTT-54. Unexpectedly, the IC₅₀for the fluoronicotinamide (LW-4-48) was found to be 0.6 nM, an approximately three-fold improvement over the preceding fluorobenzamide (SFB-CTT-54).

DEFINITIONS

A “polypeptide of 1-20 amino acids” as used herein means a linear polypeptide wherein each of the amino acids are naturally occurring or non-naturally occurring (e.g., D-amino acids, beta amino acids, beta and gamma-linked aspartate and glutamate). In certain embodiments, each of the amino acids is naturally occurring (L-amino acids). For example, a polypeptide can have the following structure, [N(R^N)—C(H)(R^A)—C(O)]_r—, wherein

- —C(O)R¹⁰is connected to the N-terminus;
- r is selected from 1 to 20;
- each R^Ais independently hydrogen, C₁-C₇alkyl, aryl, heteroaryl, arylC₁-C₇alkyl, or heteroarylC₁-C₇alkyl, wherein the alkyl, arylalkyl, and heteroarylalkyl groups are optionally substituted with 1, 2, 3, 4, or 5 R^A10groups, wherein each R^A10is independently —OR^A20, —SR^A20, —N(R^A20)₂, —C(O)OR^A20, —C(O)N(R^A2)₂, —N(R^A20)C(═NR^A2)N(R^A20)₂, or C₁-C₇alkyl, wherein each R^A20is independently hydrogen or C₁-C₇alkyl; and
- each R^Nis hydrogen,
- or any R^Aand R^Nwithin the same subunit can be taken together with the atoms to which they are attached to faun a 5 membered heterocyclyl.

“Protecting groups” include, but are not limited to substituted benzyl, t-butyl ester, alkyl esters (e.g., methyl, ethyl), and fluorenylmethoxycarbonyl groups as described in Greene's Protective Groups in Organic Synthesis, 4th Edition for protecting groups of carboxylic and phosphorus acids. Substituted benzyl groups include, but are not limited to, triphenylmethyl (trityl), diphenylmethyl, o-nitrobenzyl, 2,4,6-trimethylbenzyl, p-brornobenzyl, p-nitrobenzyl, p-methoxybenzyl, 2,6-d imethoxybenzyl, 4-(methyl sul finyl)benzyl, 4-sul fobenzyl, 4-azidomethoxybenzyl, and piperonyl, and other teachings relating to carboxylate protecting groups of Greene's Protective Groups in Organic Synthesis (included, without limitation, the identity of such groups and methods of their use) is hereby incorporated by reference in their entirety.
A “pendant group” as used herein means a group of the formula,
—(C₀-C₁₀alkyl-D)_0-1-C₀-C₁₀alkyl-,
wherein D is a bond, aryl, heteroaryl, C₃-C₈cycloalkyl, or heterocyclyl; and no more than one methylene in each alkyl group is optionally and independently replaced by —O—, —S—, —N(R⁰⁰)—, —C(H)═C(H)—, —C≡C—, —C(O)—, —S(O)—, —S(O)₂—, —P(O)(OH)—, —OP(O)(OH)—, —P(O)(OH)O—, —N(R⁰⁰P(O)(OH)—, —P(O)(OH)N(R⁰⁰)—, —OP(O)(OH)O—, —OP (O)(OH)N(R⁰⁰)—, —N(R⁰⁰)P(O)(OH)O—, —N(R⁰⁰)P(O)(OH)N(R⁰⁰)—, —C(O)O—, —C(O)N(R⁰⁰)—, —OC(O)—, —N(R⁰⁰)C(O)—, —S(O)O—, —OS(O)—, —S(O)N(R⁰⁰)—, —N(R⁰⁰)S(O)—, —S(O)₂O—, —OS(O)₂—, —S(O)₂N(R⁰⁰)—, —N(R⁰⁰)S(O)₂—, OC(O)O—, —OC(O)N(R⁰⁰)—, —N(R⁰⁰)C(O)O—, —N(R⁰⁰)C(O)N(R⁰⁰)—, —OS(O)O—, —OS(O)N(R⁰⁰)—, —N(R⁰⁰)S(O)O—, —N(R⁰⁰)S(O)N(R⁰⁰)—, —OS(O)₂O—, —OS(O)₂N(R⁰⁰)—, —N(R⁰⁰)S(O)₂O—, or —N(R⁰⁰)S(O)₂N(R⁰⁰)—, wherein each R⁰⁰is independently hydrogen or C₁-C₇alkyl.
Particular embodiments of a “pendant group” as used herein include groups of the formula,
—(C₀-C₁₀alkyl-D)_0-1-C₀-C₁₀alkyl-,
wherein

(1) D is aryl, heteroaryl, C₃-C₈cveloalkyl, or heterocyclyl; and no more than one methylene in each alkyl group is optionally and independently replaced by —O—, —S—, —N(R⁰⁰)—, —C(H)═C(H)—, —C≡C—, —C(O)—, —S(O)—, —S(O)₂—, —C(O)O—, —C(O)N(R⁰⁰)—, —OC(O)—, —N(R⁰⁰)C(O)—, —S(O)₂O—, —OS(O)₂—, —S(O)₂N(R⁰⁰)—, —N(R⁰⁰)S(O)₂—, —OC(O)O—, —OC(O)N(R⁰⁰—, —N(R⁰⁰)C(O)O—, —N(R⁰⁰)C(O)N(R⁰⁰)—, —OS(O)₂O—, —OS(O)₂N(R⁰⁰)—, —N(R⁰⁰)S(O)₂O—, or —N(R⁰⁰)S(O)₂N(R⁰⁰)—, wherein each R⁰⁰is independently hydrogen or C₁-C₇alkyl;
or
(2) D is aryl or heteroaryl; and no more than one methylene in each alkyl group is optionally and independently replaced by —O—, —S—, —N(R⁰⁰)—, —C(H)═C(H)—, —C≡C—, —C(O)—, —S(O)—, —S(O)₂—, —O(O)O—, —C(O))N(R⁰⁰)—, —OC(O)—, —N(R⁰⁰)C(O)—, —OC(O)O—, —OC(O)N(R⁰⁰)—, —N(R⁰⁰)C(O)O—, or —N(R⁰⁰)C(O)N(R⁰⁰)—, wherein each R⁰⁰is independently hydrogen or C₁-C₇alkyl;
or
(3) D is aryl or heteroaryl; and no more than one methylene in each alkyl group is optionally and independently replaced by —O—, —S—, —N(R⁰⁰)—, —C(O)—, —S(O)₂—, —C(O)O—, —C(O)N(R⁰⁰)—, —OC(O)—, or —N(R⁰⁰)C(O)—, wherein each R⁰⁰is independently hydrogen or C₁-C₇alkyl.

Particular embodiments of a “pendant group” also includes a group of the formula,
—C₀-C₁₀alkyl-,
wherein no more than one methylene in the alkyl group is optionally replaced by —O—, —S—, —N(R⁰⁰)—, —C(H)═C(H)—, —C≡C—, —C(O)—, —S(O)—, —S(O)₂—, —P(O)(OH)—, —OP(O)(OH)—, —P(O)(OH)O—, —N(R⁰⁰)P(O)(OH)—, —P(O)(OH)N(R⁰⁰)—, —OP(O)(OH)O—, —OP(O)(OH)N(R⁰⁰)—, —N(R⁰⁰)P(O)(OH)O—, —N(R⁰⁰)P(O)(OH)N(R⁰⁰)—, —C(O)O—, —C(O)N(R⁰⁰)—, —OC(O)—, —N(R⁰⁰)C(O)—, —S(O)O—, —OS(O)—, —S(O)N(R⁰⁰)—, —N(R⁰⁰)S(O)—, —S(O)₂O—, —OS(O)₂—, —S(O)₂N(R⁰⁰)—, —N(R⁰⁰)S(O)₂—, OC(O)O—, —OC(O)N(R⁰⁰)—, —N(R⁰⁰)C(O)O—, —N(R⁰⁰)C(O)N(R⁰⁰)—, —OS(O)O—, —OS(O)N(R⁰⁰)—, —N(R⁰⁰)S(O)O—, —N(R⁰⁰)S(O)N(R⁰⁰)—, —OS(O)₂O—, —OS(O)₂N(R⁰⁰)—, —N(R⁰⁰)S(O)₂O—, or —N(R⁰⁰)S(O)₂N(R⁰⁰)— wherein each R⁰⁰is independently hydrogen or C₁-C₇alkyl.
Particular embodiments of a “pendant group” also includes a group of the formula,
—C1-C₁₀alkyl-,

wherein
(1) no more than one methylene in the alkyl group is optionally replaced by —O—, —S—, —N(R⁰⁰)—, —O(O)—, S(O)₂—, —C(O)O—, —C(O)N(R⁰⁰)—, —OC(O)—, —N(R⁰⁰)C(O)—, —S(O)₂N(R⁰⁰)—, —N(R⁰⁰)S(O)₂—, —OC(O)O—, —OC(O)N(R⁰⁰)—, —N(R⁰⁰)C(O)O—, or —N(R⁰⁰)C(O)N(R⁰⁰)—, wherein each R⁰⁰is independently hydrogen or C₁-C₇alkyl;
or (2) no more than one methylene in the alkyl group is optionally replaced by —C(O)O—, —C(O)N(R⁰⁰)—, —OC(O)—, —N(R⁰⁰)C(O)—, —OC(O)O—, —OC(O)N(R⁰⁰)—, —N(R⁰⁰)C(O)O—, or —N(R⁰⁰)C(O)N(R⁰⁰)—, wherein each R⁰⁰is independently hydrogen or C₁-C₇alkyl;
or (3) no more than one methylene in the alkyl group is optionally replaced by —C(O)O—, —C(O)N(R⁰⁰)—, —OC(O)—, or —N(R⁰⁰C(O)—, wherein each R⁰⁰is independently hydrogen or C₁-C₇alkyl.

Particular embodiments of a “pend ant group” also includes a group of the formula,
-J-C₀-C₁₀alkyl-,

wherein
(1) J is —O—, —S—, —N(R⁰⁰)—, —C(H)═C(H)—, —C≡C—, —C(O)—, —S(O)—, —S(O)₂—, —P(O)(OH)—, —OP(O)(OH)—, —P(O)(OH)O—, —N(R⁰⁰)P(O)(OH)—, —P(O)(OH)N(R⁰⁰)—, —OP(O)(OH)O—, —OP(O)(OH)N(R⁰⁰)—, —N(R⁰⁰)P(O)(OH)O—, —N(R⁰⁰)P(O)(OH)N(R⁰⁰)—, —C(O)O—, —C(O)N(R⁰⁰)—, —OC(O)—, —N(R⁰⁰)C(O)—, —S(O)O—, —S(O)—, —S(O)N(R⁰⁰)—, —N(R⁰⁰)S(O)—, —S(O)₂O—, —OS(O)₂—, —S(O)₂N(R⁰⁰)—, —N(R⁰⁰)S(O)₂—, OC(O)O—, —OC(O)N(R⁰⁰)—, —N(R⁰⁰)C(O)O—, —N(R⁰⁰)C(O)N(R⁰⁰)—, —OS(O)O—, —OS(O)N(R⁰⁰)—, —N(R⁰⁰)S(O)O—, —N(R⁰⁰)S(O)N(R⁰⁰)—, —OS(O)₂O—, —OS(O)₂N(R⁰⁰)—, —N(R⁰⁰)S(O)₂O—, or —N(R⁰⁰)S(O)₂N(R⁰⁰)—, wherein each R⁰ 0 is independently hydrogen or C₁-C₇alkyl, and wherein J is bonded to the moiety substituted by the pendant group;
or (2) J is —O—, —S—, —N(R⁰⁰)—, —C(O)—, S(O)₂—, —C(O)O—, —C(O)N(R⁰⁰)—, —CO(O)—, —N(R⁰⁰)C(O)—, —S(O)₂N(R⁰⁰)—, —N(R⁰⁰)S(O)₂—, —OC(O)O—, —OC(O)N(R⁰⁰)—, —N(R⁰⁰)C(O)O—, or —N(R⁰⁰)C(O)N(R⁰⁰)—, wherein each R⁰⁰is independently hydrogen or C₁-C₂alkyl, and wherein J is bonded to the moiety substituted by the pendant group;
or (3) J is —O(O)O—, —C(O)N(R⁰⁰)—, —OC(O)—, —N(R⁰⁰)C(O)—, —OC(O)O—, —OC(O)N(R⁰⁰)—, —N(R⁰⁰)C(O)O—, or —N(R⁰⁰)C(O)N(R⁰⁰)—, wherein each R⁰⁰is independently hydrogen or C₁-C-₇alkyl, and wherein J is bonded to the moiety substituted by the pendant group;
or (4) J is —O(O)O—, —C(O)N(R⁰⁰)—, —OC(O)—, or —N(R⁰⁰)C(O)—, wherein each R⁰⁰is independently hydrogen or C₁-C₇alkyl, and wherein J is bonded to the moiety substituted by the pendant group; or (5) 7 is —C(O)N(R⁰⁰)— or —N(R⁰⁰)C(O)—, wherein R⁰⁰is hydrogen or C₁-C₇alkyl, and wherein J is bonded to the moiety substituted by the pendant group.

Particular embodiments of a “pendant group” also includes a group of the formula, —C(O)N(R⁰⁰)—C₀-C₁₀alkyl-, wherein R⁰⁰is hydrogen or C₁-C₇alkyl, and wherein the amide carbonyl is bonded to the moiety substituted by the pendant group.
Particular embodiments of a “pendant group” also includes a group of the formula,) —N(R⁰⁰)C(O)—C₀-C₁₂alkyl-, wherein R⁰⁰is hydrogen or C₁-C₇alkyl, and wherein the amide nitrogen is bonded to the moiety substituted by the pendant group.
A “pendant group comprising a detectable label, or a cytotoxic group” as used herein means a group of the formula -L-R⁰wherein L is any of the preceding pendant groups as defined herein and R⁰is a detectable label, or a cytotoxic group, each as defined above.
A “pendant group bonded to a solid support” as used herein means a group of the formula, -L-R⁰, wherein L is any of the preceding pendant groups, as defined herein, and R⁰is the surface of a solid support. Examples of solid supports include, but are not limited to, a resin, a polymer, or a silica.
The term “alkyl” as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms, unless otherwise specified. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl tert-butyl, n-pentyl, isopentyl, neop en t yl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. When an “alkyl” group is a linking group between two other moieties, then it may also be a straight or branched chain; examples include, but are not limited to —CH₂—, —CH₂CH₂—, —CH₂CH₂CHC(CH₃)—, —CH₂CH(CH₂CH₃)CH₂—.
The term “aryl,” as used herein, means a phenyl (i.e., monocyclic aryl), or a bicyclic ring system containing at least one phenyl ring or an aromatic bicyclic ring containing only carbon atoms in the aromatic bicyclic ring system. The bicyclic aryl can be azulenyl, naphthyl, or a phenyl fused to a monocyclic cycloalkyl, a monocyclic cycloalkenyl, or a monocyclic hetcrocyclyl. The bicyclic aryl is attached to the parent molecular moiety through any carbon atom contained within the phenyl portion of the bicyclic system, or any carbon atom with the napthyl or azulenyl ring. The fused monocyclic cycloalkyl or monocyclic heterocyclyl portions of the bicyclic aryl are optionally substituted with one or two oxo and/or thia groups. Representative examples of the bicyclic aryls include, but are not limited to, azulenyl, naphthyl, dihydroinden-1-yl, dihydroinden-2-yl, dihydroindcn-3-yl, dihydroinden-4-yl, 2,3-dihydroindol-4-yl, 2,3-dihydroindol-5-yl, 2,3-dihydroindol-6-yl, 2,3-dihydroindol-7-yl, inden-1-yl, inden-2-yl, inden-3-yl, inden-4-yl, dihydronaphthalen-2-yl, dihydronaphthalen-3-yl, dihydronaphthalen-4-yl, dihydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, 2,3-dihydrobenzo 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, 2,3-dihydrobenzofuran-7-yl, benzo[d][1,3]dioxol-4-yl, benzo[d][1,3]dioxol-5-yl, 2H-chromen-2-on-5-yl, 2H-chromen-2-on-6-yl, 2H-chromen-2-on-7-yl, 2H-chromen-2-on-8-yl, isoindoline-1,3-dion-4-yl, isoindoline-1,3-dion-5-yl, inden-1-on-4-yl, inden-1-on-5-yl, inden-1-on-6-yl, inden-1-on-7-yl, 2,3-dihydrobenzo[b][1,4]dioxan-5-yl, 2,3-dihydrobenzo[b][1,4]dioxan-6-yl, 2H-benzo[b][1,4]oxazin3(4H)-on-5-yl, 2H-benzo[b][1,4]oxazin3 (4H)-on-6-yl, 2H-benzo[b][1,4]oxazin3(4H)-on-7-yl, 2H-benzo[b][1,4]oxazin3 (4H)-on-8-yl, benzo[d]oxazin-2(3H)-on-5-yl, benzo[d]oxazin-2(3H)-on-6-yl, benzo[d]oxazin-2(3H)-on-7-yl, benzo[d]oxazin-2(3H)-on-8-yl, quinazolin-4(3H)-on-5-yl, quinazolin-4(3H)-on-6-yl, quinazolin-4(3H)-on-7-yl, quinazolin-4(3H)-on-8-yl, quinoxalin-2(1H)-on-5-yl, quinoxalin-2(1H)-on-6-yl, quinoxalin-2(1H)-on-7-yl, quinoxalin-2(1H)-on-8-yl, benzo[d]thiazol-2(3H)-on-4-yl, benzo[d]thiazol-2(3H)-on-5-yl, benzo[d]thiazol-2(3H)-on-6-yl, and, benzo[d]thiazol-2(3H)-on-7-yl. In certain embodiments, the bicyclic aryl is (i) naphthyl or (ii) a phenyl ring fused to either a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, or a 5 or 6 membered monocyclic heterocyclyl, wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia.
The term “arylalkyl” and “-alkylaryl” as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl.
The term “cycloalkyl” as used, herein, means a monocyclic or a bicyclic cycloalkyl ring system. Monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic. In certain embodiments, cycloalkyl groups are fully saturated. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fused bicyclic rings. Bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form —(CH₂)_w—, where w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]uonane, bicyclo[3.3.1]nonanc, and bicyclo[4.2.1]nonane. Fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. The bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. Cycloalkyl groups arc optionally substituted with one or two groups which are independently oxo or thia. In certain embodiments, the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted by one or two groups which are independently oxo or thia.
“Cycloalkenyl” as used herein refers to a monocyclic or a bicyclic cycloalkenyl ring system. Monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups are unsaturated (i.e., containing at least one annular carbon-carbon double bond), but not aromatic. Examples of monocyclic ring systems include cyclopentenyl and cyclohexenyl. Bicyclic cycloalkenyl rings are bridged monocyclic rings or a fused bicyclic rings. Bridged monocyclic rings contain a monocyclic cycloalkenyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form —(CH₂)_w—, where w is 1, 2, or 3). Representative examples of bicyclic cycloalkenyls include, but are not limited to, norbornyl and bicyclo[2.2.2]oct-2-enyl. Fused bicyclic cycloalkenyl ring systems contain a monocyclic cycloalkenyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. The bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring. Cycloalkenyl groups are optionally substituted with one or two groups which are independently oxo or thia.
The term “halo” or “halogen” as used herein, means —Cl, —Br, —I or —F.
The term “haloalkyl” as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
The term “haloalkylcarbonyloxy” as used herein means a group of the formula —OC(O)R, where R is a haloalkyl group as defined herein.
The term “heteroaryl,” as used herein, means a monocyclic heteroaryl or a bicyclic ring system containing at least one heteroaromatic ring. The monocyclic heteroaryl can be a 5 or 6 membered ring. The 5 membered ring consists of two double bonds and one, two, three or four nitrogen atoms and optionally one oxygen or sulfur atom. The 6 membered ring consists of three double bonds and one, two, three or four nitrogen atoms. The 5 or 6 membered heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heteroaryl. Representative examples of monocyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. The fused cycloalkyl or heterocyclyl portion of the bicyclic heteroaryl group is optionally substituted with one or two groups which are independently oxo or thia. When the bicyclic heteroaryl contains a fused cycloalkyl, cycloalkenyl, or heterocyclyl ring, then the bicyclic heteroaryl group is connected to the parent molecular moiety through any carbon or nitrogen atom contained within the monocyclic heteroaryl portion of the bicyclic ring system. When the bicyclic heteroaryl is a monocyclic heteroaryl fused to a phenyl ring, then the bicyclic heteroaryl group is connected to the parent molecular moiety through any carbon atom or nitrogen atom within the bicyclic ring system. Representative examples of bicyclic heteroaryl include, but are not limited to, benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, benzoxathiadiazolyl, benzothiazolyl, cinnolinyl, 5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1-yl, furopyridinyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, purinyl, 5,6,7,8-tetrahydroquinolin-2-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 5,6,7,8- tetrahydroquinol 5,6,7,8-tetrahydroisoquinolin-1-yl, thienopyridinyl, tetrahydrobenzo[c][1,2,5]oxadiazolyl, and 6,7-dihydrobenzo[c][1,2,5]oxadiazol-4(5H)-onyl. In certain embodiments, the fused bicyclic heteroaryl is a 5 or 6 membered monocyclic heteroaryl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia.
The term “heteroarylalkyl” and “-alkylheteroaryl” as used herein, means a heteroaryl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heteroarylalkyl include, but are not limited to, fur-3-ylmethyl, 1H-imidazol-2-ylmethyl, 1H-imidazol-4-ylmethyl, 1-(pyridin-4-yl)ethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, pyrimidin-5-ylmethyl, 2-(pyrimidin-2-yl)propyl, thien-2-ylmethyl, and thien-3-ylmethyl.
The term “heterocyclyl” as used herein, means a monocyclic heterocycle or a bicyclic heterocycle. The monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S where the ring is saturated or unsaturated, but not aromatic. The 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S. The 5 membered ring can contain zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. The monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle. Representative examples of monocyclic heterocycle include, but are not limited to, azctidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, imidazolinyl, isothiazolinyl, isothiazolidinyl. isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, tluazolinyl, thiazolidinyl, thionicapholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclic heterocycle fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocycle, or a monocyclic heteroaryl. The bicyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system. Representative examples of bicyclic heterocyclyls include, but are not limited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofizan-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-clihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, and octahydrobenzofuranyl. Fleterocyclyl groups arc optionally substituted with one or two groups which are independently oxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5 or 6 membered monocyclic heterocyclyl ring fused to phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroarvl, wherein the bicyclic heterocyclyl is optionally substituted by one or two groups which are independently oxo or thia.
The term “oxo” as used herein means a ═O group.
The term “saturated” as used herein means the referenced chemical structure does not contain any multiple carbon-carbon bonds. For example, a saturated cycloalkyl group as defined herein includes cyclohexyl, cyclopropyl, and the like.
The terra “thia” as used herein means a ═S group.
The term “unsaturated” as used herein means the referenced chemical structure contains at least one multiple carbon-carbon bond, but is not aromatic. For example, a unsaturated cycloalkyl group as defined herein includes cyclohexenyl, cyclopentenyl, cyclohexadienyl, and the like,
As used herein, the term “cell” is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture, In some embodiments, an in vivo cell is a cell living in an organism such as a mammal.
As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” PSMA with a compound includes the administration of a compound described herein to an individual or patient, such as a human, as well as, for example, introducing a compound into a sample containing a cellular or purified preparation containing PMSA.
As used herein, the term “individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
As used herein, the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following, as the case may be:

- (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease;
- (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder; and
- (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
  Whether the therapeutically effective amount is for prevention, inhibitions, or amelioration will be clear from the context.

As used here, the terms “treatment” and “treating” means ameliorating the referenced disease state, for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing or improving the pathology and/or symptomatology) such as decreasing the severity of disease.
As used herein, the phrase “pharmaceutically acceptable salt” refers to both pharmaceutically acceptable acid and base addition salts and solvates. Such pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sullinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC—(CH₂)_n—COOH where n is 0-4, and the like. Non-toxic pharmaceutical base addition salts include salts of bases such as sodium, potassium, calcium, ammonium, and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.

EXAMPLES

Example 1

Synthesis of Cold F19 PSMA Inhibitor

The precursor (8.9 mg, 0.00875 mmol) was dissolved in THU (2 drops) and ethanol (400 μL). A suspension of 10% Pd/C (10.9 mg/800 μL in ethanol (200 μL) and 0.0256 mmol of KHCO₃was added (25 μL of a 54.3 mg/250 μL solution), Ammonium formate (31 mg/200 μL water, 0.49 mmol) was added to initiate the reaction. The reaction was stirred at room temperature (without a cap) for 20 min, which was complete by TLC. The reaction mixture was filtered through a 0.2 μm PTFF. Whatman disc and flushed through with a mixture of ethanol: water (9:1 vol:vol ratio). The reaction mixture was evaporated to dryness and the product confirmed by ¹H and ³¹P NMR.

Example 2

Pendant Group-Bearing Precursors of PSMA Inhibitors for Indirect Labeling with ¹⁸F

PSMA inhibitors can be outfitted with a motif that could be used in click chemistry or biorthogonal click chemistry (such as the Staudinger ligation, azide-alkyne Huisgen cycloaddition, Diels-Alder, or hydrazone formation) to couple to a detectable group (fluorescent dye, covalently attached radionuclide such as ¹⁸F or ¹²³I, a chelated radioisotope such as ^99mTc, ⁶⁴Cu, ⁶⁸Ga or ¹¹¹In, a chelated MRI contrast agent, or therapeutic agent including chelated and covalently bonded radiotherapeutics such as ¹⁷⁷Lu, ⁹⁰Y, ¹²⁵I, ¹³¹I, or cytotoxic drugs like doxorubicin, camptothecin, or paclitaxel. Examples of some click chemistry handles are shown below on the CTT-54 scaffold.
Indirect 18F-radiolabeling of PSMA inhibitors such as CTT-54 can be achieved, for example, by reacting PSMA inhibitors with amine-reactive radiolabeled prosthetic groups such as N-Succiairoidyl-4-18F-Fluorobenzoate or 6-[18F]fluoronicotinic acid tetrafluorophenyl ester. See, Lapi, S. E., et al., Assessment of an 18F-labeled phosphoramidate peptidomimetic as a new prostate-specific membrane antigen-targeted imaging agent for prostate cancer. J. Nucl Med, 2009. 50(12): p. 2042-8, and Olberg, D. E., et al., One step radiosynthesis of 6-[(18)F]fluoronicotinic acid 2,3,5,6-tetrafluorophenyl ester ([(18)F]F-Py-TFP): a new prosthetic group for efficient labeling of biomolecules with fluorine-18. J Med Chem. 53(4): p. 1732-40, both of which are herein incorporated by reference.
Two alternative routes of indirect labeling which are applicable to the compounds of the present invention, including without limitation to protected or deprotected pyridine derivatives, are presented below.

Example 3

Preparation of Authentic Standards

For the single substituted nicotinamide model compounds, an authentic standard was prepared as the 6-fluoronieotinamide analog. To prepare for the labeling of the tosyloxyethylcarbamoyl benzamide from FIG. 1, we completed the preparation of the cold authentic standard as shown below.

Example 4

^99mTc-Labeling Experiments

Chelate conjugates of CTT-54 have recently been examined for the labeling of PSMA+ cells using ^89mTc as the guest radionuclide in the chelate structure. The rationale for these studies is to prepare for the development of alternative payloads for PET imaging (⁶⁸Ga or ⁶⁴Cu) and radiotherapy. ^99mTc serves as a model radionuclide for biodistribution studies.
Both LNCaP (PSIvIA+) and PC3 (PSMA−) cells were treated with DTPA-SCN-CTT-54 labeled with pertechnetate (^99mTeO₄ ⁻) reduced with SnCl₂. At increasing time points at 37° C., cells were washed free of the probe and uptake was determined as a percentage of the total amount of probe applied. Uptake was exclusive for LNCaP cells as shown in FIG. 2. Similarly, cells were treated with DTPA-SCN-CTT-54 labeled with ^99mTc(CO)₃and the data shown in FIG. 3. Preliminary studies to determine the extent of internalization of the probe were completed and the results suggest that greater than 80% internalization (See, Table 4).

TABLE 4

Time	% uptake	% internalization

30 min	2.30	71.9
2 hr	2.94	71.0
4 hr	2.34	79.5

Our data suggests that binding to the cell surface happens rapidly (within 30 min), which is followed by rapid internallization (greater than 70% within 30 min).
Competitive Binding Experiments. To confirm that the uptake of the probe was due to PSMA binding, cells were preincubated with the unlabeled inhibitor core C1T-54 for 30 min prior to incubation of the probe for 2 hours. In a dose-dependent manner, as shown in Table 5, CTT-54 blocked the binding of the radiolabeled probe.

	TABLE 5

	Concentration (nM)	% Uptake

	0	4.46
	0.5	2.80
	5	1.26
	50	0.38
	500	0.26

Biodistribution Studies. Both PSMA+ (LNCaP) and PSMA− (PC3) tumor xenografts were implanted in opposite rear flanks of each mouse. Thus, each mouse served as both a positive and negative control. In biodistribution studies with the ^99mTc-labeled probe, substantial uptake was observed in the LNCaP PSMA+ tumor xenozrafts.

Claims

1-17. (canceled)

18. A compound that is

wherein n is selected from 1-200.

19. A compound that is a pharmaceutically acceptable salt of

20. (canceled)

21. A method for detecting and/or identifying cells presenting PSMA comprising contacting a cell suspected of presenting PSMA with a compound of any one of claims 18 or 19.

22-23. (canceled)